FI85704C - Process for the preparation of therapeutically useful (4-piperidinyl methyl and hetero) purines - Google Patents

Abstract

Novel (4-piperidinylmethyl and hetero)purines of formula <CHEM> wherein -A<1>=A<2>-A<3>=A<4>- is -N=CH-N=CH- or -CH=N-CH=N- and L is a radical L<1>-CrH2r-T-CsH2s- or <CHEM> the pharmaceutically acceptable acid addition salts and possible stereochemically isomeric forms thereof, which compounds are anti-allergic agents; pharmaceutical compositions containing such compounds as an active ingredient and methods of preparing said compounds and pharmaceutical compositions.

Description

ί £ 7 O 4

Analogous Process for the Preparation of Therapeutically Useful (4-Piperidinylmethyl and Hetero) Purines U.S. Patent No. 4,219,559 describes a number of N-heterocyclyl-4-piperidineamines having antihistamine properties.

EP Patent Publication Nos. 99,139, 145,037 and 144,101 also describe a number of N-heterocyclyl-4-piper-10-diamine amines as compounds having antihitaminic and serotonin antagonistic properties.

The compounds of the present invention differ from these known compounds substantially in the nature of the 4-piperidinyl substituent, which substituent is always a purinylmethyl or hetero group.

The present invention relates to an analogous process for the preparation of novel therapeutically useful (4-piperidinylmethyl and hetero) pyrines of the formula I and their pharmaceutically acceptable acid addition salts and possible stereochemical isomers, in which the formula -A1 = A2-A3 = A4- is a divalent group of formula a-1 or a-2 30 -N = CH-N »CH (a-1) -CH = N-CH = N (a-2) wherein one of the hydrogen atoms in the group of formula a-1 or a-2 may be replaced by C 1-4 alkyl,: C 1-4 alkyloxy or hydroxy; R 15 is C 1-6 alkyl, C 3-6 cycloalkyl or Ar 1 -C 1-4 alkyl, wherein Ar 1 is thienyl, pyridinyl, pyrazinyl, thiazolyl, furanyl, C 1-6 alkyl substituted furanyl, phenyl or phenyl substituted halogen, C 1-4 alkyl or C 1-4 alkyloxy; R 2 is hydrogen or C 1-4 alkyl; B is -CH 2 -, -s-, -O- or -NH-; L is a group of formula b-1 L1-tC, H2b- (b-1) wherein s is an integer from 1 to 6, T is -Y- or -ZC (-X) -Y-, wherein Y is straight a bond or NR3, Z is a direct bond or NR3 and X is O or S, wherein R3 is hydrogen or C1-4alkyl; and L1 is hydrogen; hydroxy; C 1-4 alkyloxy; C 2-5 alkenyl; phenyl; phenyl substituted by hydroxy, amino, C 1-4 alkyl or C 1-4 alkyloxy; furanyl; thienyl; pyridinyl optionally substituted with amino; pyrimidine-pyridinyl; morpholinyl; 2,3-dihydro-l, 4-benzodioxinyl;

2-oxo-2H-l-benzopyranyl; thiazolyl; 4,5-dihydro-5-oxo-1H-tetrazolyl substituted with C1-4 alkyl; or · · a group of formula e-1, e-4, e-7 or e-8; : H

: '' Ί ^ νΝν °; (M) · tX / - ('· 4)

77. 30 0 O

'7 CQ- (c-7) qcv »^ -35 wherein G2 is -CH« CH-CH «CH-, - (CH2) 4- or -S-CH-CH-.

3 65 704

To more simply illustrate the structure of the compounds of formula I and certain precursors and intermediates thereof, the 6-tVS of formula; The group according to 10 is represented below by the symbol D.

In the above definitions, the term halogen includes fluorine, chlorine, bromine and iodine; the term "C alkyl" embraces straight and branched chain saturated hydrocarbon groups having from 1 to 6 carbon atoms; examples are methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, 2-methylpropyl, butyl, pentyl and hexyl; the term "C 2-5 alkenyl" embraces straight and branched chain hydrocarbon groups having from 2 to 5 carbon atoms; Examples thereof include 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and the like; the term "C 3-6 cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and "C 2-6 alkanediyl" means divalent straight or branched chain alkanediyl groups having from 2 to 6 carbon atoms.

The most preferred compounds of formula I are those wherein R 1 is Ar 1 -C 1-4 alkyl.

Compounds of formula I wherein L 1 is amino-substituted pyridinyl may contain the structure. 30 keto-enol tautomeric system or its viny-log system, so that these compounds may be present in the keto-enol tautomeric system. in its form, as well as in its enol form.

The process according to the invention for the preparation of the compounds of the formula I is characterized in that a) N-alkylation of piperidine of the formula I-c-1 4 I / 7 O 4 H-D (I-c-1) in which D is a group of the formula R 2 R 1

5 / “K N

-N Ub- ^ Va1 \ / \\ // ^ a2 N— \ / A <= A3 where -A1 = A2-A3 = A4-, R1, R2 and B have the same meaning as in formula I, in an inert organic solvent reagent- for formula VII-a L1-TC, H2i-W (VII-a) wherein L1, T and s are as defined in formula I and H is a reactive leaving group; b) alkylating piperidine of formula Ic-2 H-T2-C.H2, -D (Ic-2) 2 O wherein T2 is -NR3- or -NR3-C ((X) -Y- and s, R3, X and Y are as defined in formula I, in an inert organic solvent with a reagent of formula VII-b L 1 -W (VII-b) wherein L 1 "* is pyrimidinyl or thiazolyl and W is a reactive leaving group to give a compound having of formula Ibla 30 ΐ / - “- Τ2-θ.Η2.-ϋ (Ibla); c) N-alkylation of piperidine of formula Ic-1.35 HD (Ic-1) 5 6 5 7 04

in a reaction-inert solvent with a carbonyl compound of formula VIII

L1-TC, H2, .1 * 0 (VIII) 5 which compound of formula VIII is a reagent of formula L1-TC, H2e4l 10 in which L1, T and s have the same meaning as in formula I and in which the group -CH2- is substituted by carbo -nyyliryhmällä;

d) introducing an amine of formula XI

Ι ^ -νη2 (XI) wherein L1 is as defined in formula I, to react in a reaction-inert solvent with an isocyanate or isothiocyanate of formula If X = C = NC, H2a-D (If) wherein X and s are as defined in in formula I to give a compound of formula Ib-4 L-NH-C (= X) -NH-C.H2, -D (Ib-4); e) introducing an isocyanate or isothiocyanate of formula 30

TF-N-C-X

wherein L1 and X are as defined in formula I, to react in an inert solvent with an amine 35 of formula Ic-4 6>: / o 4 H2N-C.H2 „-D (Ic-4) wherein s is as defined in formula I to give a compound of formula Ib-4;

5 f) reacting a reagent of formula XIII

1 / -O (= X) -OH (XIII) wherein L1 and X are as defined in formula I, reacts with the amine of formula Ic-4 in a reaction-inert solvent, if desired after the OH- the group is converted to a reactive leaving group, or by reacting a reagent of formula XIII with an amine of formula Ic-4 in the presence of a reagent capable of forming esters or amides to give a compound of formula Ib-6-a 1 / -O (= X) -NH-C.H2, -D (Ib-6-a); 20

g) subjecting my intent to formula XIV

L1-T-C2-6-alkenediyl-H (XIV) -25 to react in a reaction inert solvent with piperidine of formula HD (Ic-1) to give a compound of formula Ig L1-T-C2. 6-alkanediyl-D (Ig); h) introducing piperidine of formula I-c-1

To react in a reaction-inert solvent with an oxirane of formula XV

7 t o / O 4 Λ H2C-CH2 (XV) to give a compound of formula i-h 5 HO-CH2-CH2-D (I-h); or i) silylodesulfurizing a thioamide of formula

10 XXXVII

llY s (XXXTO)

B

In a reaction-inert solvent with a suitable alkyl halide, metal oxide or metal salt to give a compound of formula I-i-11

20 H

or optionally converting compounds of formula I to each other by art-modification methods known in the art, and if desired converting compounds of formula I to therapeutically active, non-toxic acid addition salts by treatment with a suitable acid, or converting the acid addition salt to the free base with an alkali; 30 and / or stereochemically isomeric forms of the compounds of the formula I are prepared.

In some cases, the alkylation reagent (VII-a) may also be a reactive cyclic reagent which may be formed by an intramolecular cyclization reaction. Said cyclic form (VII-a) may be formed in situ or, if desired, may be isolated and further purified prior to reaction with a compound of formula (I-c-1).

The alkylation reactions according to process variants a) and b) are suitably carried out in an inert, organic solvent, examples of which are aromatic hydrocarbons, e.g. benzene, methylbenzene, dimethylbenzene and the like; C 1-4 alkanols, e.g. methanol, ethanol, 1-butanol and the like; ketones, e.g. 2-propanone, 4-methyl-2-pentanone and the like; ethers, e.g. 1,4-dioxane, 1,1'-oxybis-10-ethane, tetrahydrofuran and the like; N, N-dimethylformamide (DMF); Ν, Ν-dimethylacetamide (DMA); dimethyl sulfoxide (DMSO); nitrobenzene; 1-methyl-2-pyrrolidinone and the like. In addition, a suitable base such as an alkali metal carbonate or bicarbonate, sodium hydride or an organic base such as N, N-dimethylethanamine or N- (1-methylethyl) -2- propanamine, to bind the acid released in the reaction. In some cases, it is convenient to add an iodide salt, preferably an alkali metal iodide. A somewhat elevated temperature may no-20 dampen the reaction.

The reductive N-alkylation reaction according to process variant c) can be conveniently carried out catalytically by hydrogenating a mixture of reactants in a suitable reaction-inert organic solvent according to the art. 25 known catalytic hydrogenation methods. The reaction mixture may be stirred and / or heated to accelerate the reaction. Suitable solvents include, for example, water; C 1-4 alkanols, e.g. methanol, ethanol, 2-propanol and the like, cyclic ethers, e.g. 1,4-dioxane and the like. halogenated hydrocarbons, e.g., trichloromethane, etc., N, N-dimethylformamide, dimethyl sulfoxide, etc., or mixtures of two or more such solvents The term "catalytic hydrogenation methods known in the art" means that the reaction is carried out under an atmosphere of a suitable catalyst. in the presence of, for example, palladium / carbon, * ... · platinum / carbon, etc. In order to avoid undesired hydrogenation of certain functional groups in the reactants and reaction products, it may be advantageous to add a suitable catalyst to the reaction mixture. a poison such as thiophene or the like.

The reactions according to process variants d) and e) can be carried out in a suitable reaction-inert solvent, examples of which are hydrocarbons, e.g. benzene, ketones, e.g. acetone, halogenated hydrocarbons, e.g. dichloromethane, trichloromethane, ethers, e.g. 1,1'- 10 oxybisethane, tetrahydrofuran, etc. Elevated temperature may accelerate the reaction.

The reaction according to process variant f) can generally be carried out following esterification and amidation reaction methods known in the art. For example, a carboxylic acid can be converted to a reactive derivative, for example an anhydride or carboxylic acid halide, which is then reacted with a compound of formula Ic-4 or a compound of formula XIII is reacted with a compound of formula Ic-20. 4 using a suitable reagent capable of forming amides or esters, e.g. dicyclohexylcarbodiimide, 2-chloro-1-methylpyridinium iodide, etc. These reactions are preferably carried out in a suitable solvent, examples of which include ethers, e.g. tetrahydrofuran, halogenated hydrocarbons. , e.g. dichloromethane, dichloromethane, polar aprotic solvents, e.g.

N, N-dimethylformamide. It may be appropriate to add a base to the reaction, e.g. N, N-dimethylethanamine.

Reactions 30 according to process variants g) and h) can be carried out by stirring and, if desired, heating the reactants together. These reactions can be carried out in a suitable solvent such as alkanones, e.g. 2-propanone, 4-methyl-2-propanone, ethers, e.g. tetrahydrofuran, 1,1'-oxybisethane, alcohols, e.g. methanol, ethanol, 1-butanol, N, N-dimethylformamide, N, N-dimethylacetamide and the like.

15 7 04 ίο

According to process variant i), cyclodesulfurization of a thioamide of formula XXXV11 can be carried out by reacting compound (XXXVII) with a suitable alkyl halide, preferably iodomethane, in a suitable reaction-inert organic solvent, e.g. C 1-4 alkanol such as methanol, ethanol, 2-propanol. Alternatively, cyclodesulfurization can be performed by reacting compound (XXXVII) with a suitable metal oxide or salt in a suitable solvent in a manner known in the art. For example, a compound of formula I can be readily prepared by reacting compound (XXXVII) with a suitable oxide or salt of Hg (II) or Pb (II), examples being HgO HgCl2, Hg (OAc) 2, PbO or Pb (OAc) 2 . In some cases, it may be advantageous to add a small amount of sulfur to the reaction mixture. However, methanediimines, especially N, N'-methanetetrylbis [cyclohexanamine], can also be used as cyclodesulfurizers. Elevated temperature can be used to accelerate the reaction.

The compounds of formula I may also be converted into each other following art-known procedures for converting functional groups. The following are some • examples.

Compounds of formula I having an ester group may be converted to the corresponding carboxylic acids by saponification methods known in the art, e.g. by treating these compounds with an aqueous alkali solution or an aqueous acid solution.

The halogen atoms which are substituents on the phenyl group can be replaced by hydrogen by hydrogenolysis methods known in the art, i.e. by stirring and, if desired, heating the starting compounds, e.g. in the presence of a palladium / carbon catalyst or the like. Halogen atoms can also be replaced by a C 1-4 alkyloxy substituent by reacting the starting halogen compound with a suitable alcohol 11 ε £ 7 O 4 or preferably with an alkali or alkaline earth metal salt of a suitable alcohol in a suitable solvent.

In compounds of formula I which contain an imino group, e.g. in compounds where NR1 or NR3 is NH5 or which contain an amino group, e.g. in which L1 is substituted by an amino group, the hydrogen atom in the imino or amino group may be replaced by a suitable substituent in a manner known in the art, e.g. by alkylation, reductive N-alkylation, acylation and the like.

10 Several such methods are described in detail below. The C 1-6 alkyl group or the substituted C 1-6 alkyl group may be attached by reacting the starting compound with a suitable N-alkylating agent by the method described above in connection with process options a) and b), or by reacting the starting compound with a suitable carbonyl compound and then carrying out an N reductive alkylation by the method described above in connection with process variant c).

C 1-6 alkylcarbonyl and the like may be incorporated by reacting the starting amine with a suitable carboxylic acid or derivative thereof, for example, an acid halide, acid anhydride, and the like.

The C 1-4 alkyloxycarbonyl groups can be attached by reacting the starting amine compound with a suitable halocarbonate, e.g., ethyl halocarbonate, phenylmethyl halocarbonate, and the like.

Ar 2 -NH-CO and Ar 2 -NH-CS, wherein Ar 2 is L 1 which is phenyl, substituted phenyl, thienyl or furanyl, and the like can be suitably attached by reacting the starting amine with a suitable isocyanate or isothiocyanate according to process options d) above. and e) the method described herein.

Compounds of formula I having a substituted nitrogen atom may be converted to the corresponding compounds of formula I in which a hydrogen atom is attached to the nitrogen atom, for example when the nitrogen atom is substituted by Ar 2 -CH 2, in a manner known in the art for the preparation of NH groups. by treating the starting compound with hydrogen in the presence of a suitable catalyst, e.g. Pd / C, Pt / C catalyst or the like, in a suitable solvent.

In all of the above and subsequent preparations, the reaction products can be isolated from the reaction mixture and, if necessary, further purified by methods generally known in the art.

The compounds of formula I are basic in nature and can thus be converted into their therapeutically active acid addition salts by treatment with suitable acids, examples of which are inorganic acids such as hydrohalic acids, e.g. hydrochloric acid, hydrobromic acid, etc. and sulfuric acid, nitric acid, etc. such as acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, acetic acid, propanedioic acid, butanedioic acid, 20 (Z) -2-butenedioic acid, (E) -2-butenedioic acid, 2-hydroxybutanoic acid, 2,3- dihydroxybutanedioic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxy-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2-hydroxybenzoic acid

Conversely the salt form can be converted by treatment with alkali into the free base form.

In the above preparations, some of the intermediates and starting materials are known compounds that can be prepared by methods known in the art to prepare these or similar compounds, and others are novel compounds. Several such methods are described in more detail below.

The starting compounds of formula I ', i.e. formula Ic-1, Ic-2, Ic-4, If, Ig or i3 £ 5 704 Ih can be prepared by reacting a piperidine of formula II with a diamine of formula III r2 X1 r1 1 / ~ f \ Il A ^ A2. Y -> (II) (III)

In some cases, the reaction between compounds of formulas II and III first yields an intermediate of formula II-a 2 1 1, 1 is lh / KJL_J [i3 (I1'a> -> u,> v_y h which may be used in situ or if desired isolated and further purified to cyclize to the desired starting compound of formula I *.

In formulas II and II-a, X 1 is O, S or NH.

In the above and following reaction schemes, W is a suitable leaving group such as halogen, e.g. chlorine, bromine or iodine, sulfonyloxy group, e.g.

Methylsulfonyloxy or 4-methylphenylsulfonyloxy, and when W is attached to a -C (= X *) - group it may also be C 1-6 alkyloxy, C 1-6 alkylthio, Ar 2 -O- or Ar 2 -S-.

The piperidine of formula II can be formed in situ, for example, by converting a piperidine having a substituent -B-C (> X1) -OH at the 4-position to a piperidine of formula II by reaction with thionyl chloride, phosphorus trichloride, phosphoryl chloride, polyphosphoric acid, phosphorus oxychloride or the like.

The reaction between compounds of formulas II and III may be carried out in a suitable solvent, examples of which are hydrocarbons, e.g. benzene, hexane, ethers, e.g. 1,1'-oxybisethane, tetrahydrofuran, ketones, e.g. 2-propanone, 2- butanone, alcohols, e.g. methanol, ethanol, 2-propanol, 1-butanol, halogenated hydrocarbons e.g. trichloromethane, dichloromethane, organic acids e.g. e.g. acetic acid, propanoic acid, polar aprotic solvents e.g. e.g. N, N-dimethylformamide, Ν, Ν-dimethylacetamide, etc., and mixtures of such solvents. Depending on the solvent and the nature of W, it may be advantageous to add a suitable base and / or iodide salt, preferably an alkali metal iodide, to the reaction mixture. Elevated temperature may accelerate the reaction.

Compounds of formula I 'may also be prepared by reacting an intermediate of formula V with a piperidine of formula IV, wherein E1 and E2 are selected so as to form a group -B- in the reaction.

20 K> 1 + -> «'A4 ^ (IV) (V)

For example, a compound of formula 1 'can be prepared by reacting a piperidine of formula IV wherein E1 is a group of formula -B-M with an intermediate of formula V wherein E2 is a group of formula -W.

ί X 7 30 LN ^^^ - BM + W ~ -> (1 ') A i? - (IV-a): (Va): In formula IV-a M is, depending on the nature of B, hydrogen 35 or a suitable alkali metal or alkaline earth metal, and in the formula Va W denotes the above. In addition, compounds of formula 15704 I 'can also be prepared by reacting a piperidine of formula IV wherein E1 is W with an intermediate of formula V wherein E2 is a group of formula -B-M, wherein W and 5 M are as defined above.

R2 1 / "K I A1 2 \ _ / Il || | 3 -> (I ')

N -Λ V

10 (IV “b) (V-b)

Compounds of formula 1 'wherein B is -CH 2 - can also be prepared by reacting a piperidine of formula IV wherein E 1 is a group of formula 15 -CH 2 -W, i.e. a compound of formula IV-c, by reacting an intermediate of formula V with where E2 is M, i.e. with a compound of formula Vc, or alternatively by reacting a piperidine of formula IV wherein E1 is a group of formula -M, i.e. a compound of formula IV-d with such an intermediate of formula V, wherein E2 is a group of formula -CH2-W, i.e. with a compound of formula Vd.

25 K2 R1,

: / - V 1 V

L-N VcH - W +.

N ^ A ^ * (IV-c): (Vc) R 1: "h ,, 1 - / ^ -« * ν- € Η2η '“· γ <I-«) 35 N ^ 4> (IV-d ) (Vd) 16 1:704

The reaction between compounds of formulas IV and V may conveniently be carried out in a suitable solvent, examples of which are aromatic hydrocarbons, e.g. benzene, methylbenzene, ethers, e.g. 1,4-5 dioxane, 1,1'-oxybisethane, tetrahydrofuran and the like, hydrogenated hydrocarbons, e.g. trichloromethane and the like, N, N-dimethylformamide (DMF), Ν, Ν-dimethylacetamide (DMA), and when M is hydrogen, the solvent may also be a C 1-4 alkanol, e.g. methanol, ethanol, 1- butanol and the like, a ketone, e.g. 2-10 propanone, 4-methyl-2-pentanone and the like. In some circumstances it may be appropriate to add a suitable base such as an alkali metal carbonate or bicarbonate, sodium hydride or an organic base, for example Ν, Ν- diethylethanamine or N- (1-methylethyl) -2-propan-15-amine and / or iodide salt, preferably alkali metal iodide. Somewhat elevated temperatures may accelerate the reaction.

Compounds of formula 1 'wherein B is NH may also be prepared by cyclodesulphurisation of a suitable thiourea derivative of formula kSp *

B

(VI-a) This cyclodesulfurization reaction can be carried out by reacting a compound of formula VI-a with a suitable alkyl halide, preferably iodomethane, in a suitable reaction-inert organic solvent, e.g. C 1-6 alkanol such as methanol, ethanol, 2-propanol and the like. the cyclodesulfurization reaction can be carried out by reacting a compound of formula VI-a with a suitable metal oxide or salt in a suitable solvent in a manner known in the art. Esi- e; 704 17 compounds of formula I 'can be readily prepared by reacting a compound of formula VI-a with a suitable oxide or salt of Hg (II) or Pb (II), examples being HgO, HgCl2, Hg (Oac) 2, PbO 5 and Pb (OAc) 2. In some cases, it may be appropriate to add a small amount of sulfur to the reaction mixture. Methane diimines, especially N, N'-methanetrayylbis [cyclohexanamine], can also be used as cyclodesulfurizing agents.

In some cases, compounds of formula I 'wherein B is NH may alternatively be prepared by cyclodesulphurisation of a thiourea of formula VI-b followed by dehydration of the oxazole [5,4-d] pyrimidine derivative thus obtained with a suitable dehydrating agent, e.g. phosphoryl chloride, phosphorus trichloride-15a, phosphorus pentachloride, thionyl chloride and the like.

.Aj: ¾¾ \ _ / i li-T ^

20 H R OH

(VI-b)

In formula VI-b, R1_ "has the same meaning as R1 above. The compounds of formula I 'may also be converted into each other.

Compounds of formula 1 'in which L1 is a thiazolyl group may be prepared by a variety of cyclization reactions to give compounds of formula (I-i-2) or (I-i-3), as the case may be.

30 H-CH-C-H + H ^ N-C-K-D cyclization-v (<SvifK ° i S I -asas—> Li (XVII) (XVIII) (I-i-2)

H II

H-C-NH "+ W-CH-C-K-D x 1 'I

2 -> N -K-D

(XIX) (XX) · ;;;. · A-i-3) 18 fc: 3/04

Further, when L1 is a group of formula e-1, L1 can be formed by condensing an intermediate of formula XXI with a group> C = O-producing agent, exemplified by urea, 1,1'-carbonylbis [1H-imidazole], 5 Ci.g. -alkyl halocarbonate, phosgene, trichloromethyl halocarbonate and the like.

Of2 - - 00-

l ^> k C-NH-C-D

0 β-producing λ (XXI) substance (I-i-4)

Compounds of formula I-i-4 may further be prepared by cyclization of an intermediate of formula

O

10 X \ JH-C-NH-K-D

YXX: -w

B

O

which can be prepared in situ by reacting a reagent of formula XXIII with an amine of formula XXIC.

aN = C = O + H2N-K-D - »(XXII).

f_w (XXIV) (XXIII) p

The reaction between a compound of formula XXI (XXI) and a compound producing a> C = O group can preferably be carried out in a suitable solvent such as ethers, e.g. 1,1-oxybisethane, tetrahydrofuran, halogenated hydrocarbons, e.g. dichloromethane, trichloromethane. methane, hydrocarbons, e.g. benzene, methylbenzene, alcohols, e.g. methanol, ethanol, ketones, e.g. 2-propanone, 4-methyl-2-pentanone, N, N-dimethylformamide, 35β, N-dimethylacetamide, and mixtures of these solvents, optionally in the presence of a suitable base, for example in the presence of N, N-di-19 L · c / O 4 ethyllethanarine, alkali or alkaline earth metal carbonate or bicarbonate. To speed up the reaction, it may be advantageous to heat the reaction mixture.

When L1 is a group of formula e-7, L1 is formed by cyclodesulfurization of an intermediate of formula XXXVII to give a compound of formula I-i-11.

B

αNH2 cycodesulfurization [l l |

nh-c-k-d reaction -N

II

(XXXVIT) O (I-i-11)

Intermediates of formula II wherein B is CH 2, X 1 is NH and W is C 1-6 alkyloxy, which intermediates are represented by formula II-c, can be prepared by reacting (cyanomethyl) piperidine of formula XXXIX with an alcohol, e.g. methanol, ethanol and the like. in the presence of an acid, e.g. hydrochloric acid.

R

20 / T 1 acid L-N 2 -CH 2 CN + C 1-6 alkanol->

(XXXIX) R

aAv ψ1 25 L-N) -C 1 -C-O-C 1-6 alkyl (II-c)

Intermediates of formula IV can be prepared by reduction of the appropriate 4-piperidinone, and if desired by subsequent suitable group exchange reaction known in the art, e.g. to prepare a compound of formula Vb, the resulting alcohol is reacted with thionyl chloride, methylsulfonyl chloride or the like to give the appropriate leaving group. .

35 20 (: 0 4

Intermediates of formula VI-a can be prepared, for example, by the methods described in EP patents 99 139, 145 037 and 144 101.

Intermediates 5 of formulas VII-a and VII-b can be conveniently prepared by methods known in the art, as described, for example, in U.S. Patent Nos. 4,335,127 and 4,342,870 and EP 70,053.

It can be seen from formula I that the yh-10 dysts of formula I may have several asymmetric carbon atoms in the structure. Each of these chiral centers may be in the R or S configuration; this R or S configuration is denoted according to R.S. In Cahn, C. Ingold, and V. Prelog, Angew. Chem., Int. Ed. Engl., 5.

15 385, 511 (1966).

Pure stereochemically isomeric forms of formula I may be obtained by the application of art-known procedures. Diastereoisomers may be separated by physical methods such as selective crystallization and chromatography, e.g. countercurrent distribution, and enantiomers may be selectively separated by crystallization of their diastereomeric salts with optically active acids.

Pure stereochemically isomeric forms may also be prepared from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.

It will be appreciated that the cis and trans diastereomeric racemates may be further subdivided into their optical isomers, cis - (+), cis (-), trans - (+) and trans (-) isomers by methods known to those skilled in the art. .

Stereochemically isomeric forms of the compounds of formula I are obviously intended to be embraced within the scope of this invention.

The compounds of formula I have useful pharmacological properties; they are active antihistamines and serotonin antagonists. This is clearly demonstrated by the results of the experiment "Protection of rats from 48/80 death".

Based on their antihistamine properties, the compounds of formula I 5 and their acid addition salts are very useful in the treatment of allergic diseases such as allergic rhinitis, allergic conjunctivitis, chronic urticaria, allergic asthma and the like.

10 Pharmacological examples

The useful antihistamine properties of the compounds of formula I were demonstrated by the following test method.

Protection of rats against death due to compound 48/80_

Compound 48/80, an oligomer obtained by the condensation of 4-methoxy-N-methylbenzenethanamine and formaldehyde, has been described as an active histamine-releasing agent (Int. Arch. Allergy, 13, 336 1958). The retention of Suo-20 from the lethal circulatory collapse caused by compound 48/80 appears to be a simple means of quantifying the antihistamine activity of test compounds. Male closed-breed Wistar rat rats weighing 240-260 g were used in the experiment. The rats were fasted overnight, then transferred to air-conditioned laboratories (temperature 21 ± 1 ° C, relative humidity 65 ± 5%). Rats received subcutaneously or orally the test compound or solvent (0.9% NaCl solution. One hour after treatment, rats were injected intravenously with a reconstituted solution of 48/80 at a dose of 0.5 mg / kg (0.2 ml / 100 g body weight) In control experiments in which 250 solvent-treated rats received a standard dose of 48/80, only 2.8% of the animals received more than 4 hours.

35 Survival of more than 4 hours is then considered a safe criterion for the protective effect of drug administration.

ε 5 7 O 4 22

The ED50 values for the compounds of formula I are summarized in Table 1. These ED50 values indicate the amount of test compound in mg / kg body weight which protects the test animals from death caused by compound 48/80.

5 Table 2, in turn, summarizes some of the formula I

In addition to the ED50 values of the compounds according to the invention, the ED50 values of some known compounds with a similar structure are similar. Based on these results, it can be concluded that the new compounds of formula I have significantly better antihistamine properties than the known reference compounds a-f.

23 l: 70 4

table 1

Compound No. ED 1 values in rats mg / kg body weight __ in the 4ο / 80 lethality test 60 0.08 61 0.01 62 0.04 64 0 r08 74 0.01 75 0.08 76 0.02 77 0.02 78 0.04 79 0.04 80 0.04 81 0.04 83 0.08 87 0.08 88 0.02 89 0.08 100 0.02 104 0.04 106 0.08 107 0.02 114 0 04 115 0.08: 141 0.01 142 0.02 143 0.02 144 0.04 145 0.01 165 0.02 167 0.08 168 0.02 169 0108 171 0.08 172 0.04 173 0 .08 183 0.04 I 3 7 0 4 24 ^ «CM fd -P oo

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Due to their good pharmacological properties, the compounds of the formula I can be formulated into various pharmaceutical forms suitable for administration. To prepare such pharmaceutical compositions, an effective amount of the subject compound in base form or in the form of an acid addition salt as the active ingredient is mixed with a highly pharmaceutically acceptable carrier, which carrier may vary in form depending on the form of preparation desired for administration. These pharmaceutical compositions are preferably in unit dosage form suitable for oral, rectal, percutaneous administration or parenteral injection. For example, in preparing the compositions for oral administration, any of the usual media may be employed, for example, water, glycols, oils, alcohols, etc., in the case of oral liquid compositions such as suspensions, syrups, elixirs, and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. In parenteral compositions, the carrier will usually comprise at least a large amount of water, although other ingredients, for example, to aid solubility, may be included in the compositions. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. In compositions suitable for percutaneous administration, the carrier may contain a wetting agent and / or a suitable wetting agent. and possibly small amounts of additives of different natures that do not significantly damage the skin. Such additives may facilitate the administration to the skin and / or may be helpful for preparing the desired composition. Such compositions may be applied in various ways, e.g., as transdermal patches, as immediate release preparations, as ointments. Because the acid addition salts of the compounds of formula I have better water solubility than the corresponding bases, the acid addition salts 10 are obviously more suitable for the preparation of aqueous compositions.

For ease of administration and uniformity of dosage, it is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form. Dosage unit as used in the specification and claims refers to physically discrete units suitable as unitary dosages, each containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoons, tablespoons and the like.

Koostumusesimerklt

The following compositions are exemplary of pharmaceutical compositions in unit dosage form suitable for systemic administration of a compound of formula I to animal or human subjects.

As used in these examples, the term "Active Ingredient" (A.I.) means a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.

: ·.! 35 27 85 704

Example A: Oral drops 500 g of A.I. were dissolved at 60-80 ° C in a mixture of 2-hydroxypropanoic acid (0.5 L) and polyethylene glycol (1.5 L). The mixture was cooled to 30-40 ° C, 35 L of polyethylene glycol was added, and the mixture was stirred well. A solution of Na-saccharin (1750 g) in 2.5 L of purified water was then added with stirring to 2.5 L of cocoa flavor and polyethylene glycol to a volume of 50 L to give an oral drop solution containing 10 mg / ml A.I. The resulting solution was filled into suitable containers.

Example B: Oral solution 9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate were dissolved in 4 liters of boiling purified water. To 3 liters of this solution was dissolved first 10 g of 2,3-dihydroxybutanedioic acid and then 20 g of A.I. The last solution obtained and the remainder of the first prepared solution were combined, and 12 l of 1,2,3-propanetriol and 3 l of a 70% sorbitol solution were added to the combined solution. 40 g of Na-saccharin was dissolved in 0.5 liter of 20 water, and 2 ml of raspberry essence and 2 ml of gooseberry essence were added to the solution. The latter solution was combined with the previously prepared and to the combined solution was added water to a volume of 20 liters to give an oral solution containing 20 mg of A.I. in a solution of teaspoonful (5 ml). The resulting solution was filled into suitable containers.

Example C: Capsules / - 20 g A. From, 6 g of sodium lauryl sulphate, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silica and 1.2 g of magnesium stearate were mixed well. The resulting mixture was then filled into 1000 suitable hard gelatin capsules to give capsules each containing 20 mg of A.I.

• * · 35 28 8 5/04

Example D: Film-coated tablets

Preparation of tablet core 100 g of A.I., 570 g of lactose and 200 g of starch were mixed well together, the mixture was then moistened with a solution containing 5 g of sodium dodecyl sulphate, 10 g of polyvinylpyrrolidone (Kollidon-K 90®) and about 200 ml of water. The wet powder mixture was screened, dried and rescreened. 100 g of microcrystalline cellulose (Avicel®) and 15 g of hydrogenated vegetable oil 10 (Sterotex®) were then added. The mixture was mixed well and compressed into 10,000 tablets, each containing 10 mg of A.I.

Pavement

To a solution of methylcellulose (Methocel 60 HG® (10 g) in 75 ml of denatured ethanol was added a solution of ethylcellulose (Ethocel 22 cp®) (5 g) in 150 ml of dichloromethane. Then 75 ml of dichloromethane and 2 5 ml of 1,2,3-propanetriol 10 g of polyethylene glycol were melted and dissolved in 75 ml of dichloromethane.

The latter solution was combined with the previously prepared one and then 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of a concentrated color suspension (Opaspray Kl-2109® were added and the mixture was homogenized. The tablet cores were coated with the mixture thus obtained in a coating machine). .

V Example E: Solution for injection 1.8 g of methyl 4-hydroxybenzoate and 0.2 g of propyl 4-hydroxybenzoate were dissolved in about 0.5 liters of boiling water for injection. The solution was allowed to cool to about 50 ° C, then 4 g of lactic acid, 0.05 g of polyethylene glycol and 4 g of A.I. were added with stirring.

The solution was cooled to room temperature and into it. ’. water for injection was added to a volume of 1 liter t · · * · · ·> · · • · · 29 f. C 7 r - * 'O / L. · · to obtain a solution containing 4 mg / ml AI . The solution was sterilized by filtration (U.S.P. XVII p.

811) and filled into sterile containers.

Example F; Suppositories 5 3 g of A.I. were dissolved in a solution of 2,3-dihydroxybutanedioic acid (3 g) in 25 ml of polyethylene glycol 400.

12 g of surfactant (Span®) and triglycerides (Witepsol 555®) q.s. Melted to 300 g. The latter mixture was mixed well with the first 10 prepared solutions. The mixture thus obtained was poured into molds at 37-38 ° C to obtain 100 suppositories, each containing 30 mg of A.I.

For the treatment of allergic diseases in warm-blooded animals, they may be administered an effective antiallergic amount of a compound of formula I or a pharmaceutically acceptable acid addition salt thereof. An expert in warm-blooded animals with allergic diseases can readily determine an effective amount based on the experiments described above. In general, an effective amount is 0.1 to 100 mg, more preferably 1 to 50 mg.

The following examples illustrate the invention. Unless otherwise stated, all parts are by weight.

Experimental Part A. Preparation of intermediates Example 1 2-Pyridinemethanamines (3.7 parts), 4,6-dichloropyrimidin-5-amine (4.1 parts), N, N-diethylethanamine (3.03 parts) and the mixture of water (150 parts) was stirred for 8 hours at room temperature. After cooling, the mixture was stirred overnight. The product was filtered, washed with water and dried overnight in vacuo at 80 ° C to give 5.35 parts (90.8%) of 6-chloro-N4- (2-pyridinylmethyl) -4,5-pyrimidinamine. , sp. 140.3 ° C (interm. 1).

In a similar manner there were also prepared: 4-3065704 6-chloro-N - [(4-fluorophenyl) methyl] -4,5-pyrimidinediamine, m.p. 244.4 ° C (interm. 2); 6-chloro-N4- (2-furanylmethyl) -4,5-pyrimidinediamine, m.p. 138.7 ° C (interm. 3); 6-chloro-N4- (2-thienylmethyl) -4,5-pyrimidinediamine, m.p. 165.5 ° C (interm. 4); 6-chloro-N4- (75-methyl-2-furanyl) methyl-4,5-pyrimidineamine (interm. 5); 6-chloro-N4- (2-pyrazinylmethyl) -4,5-pyrimidinedi-10-amine (interm. 6); 6-chloro-N4- (4-thiazolylmethyl) -4,5-pyrimidinediamine, m.p. 145.4 ° C (interm. 7); 6-chloro-N4 - [(4-methoxyphenyl) methyl] -4,5-pyrimidinediamine; mp 183.5 ° C (interm. 8); and N4- (T4-fluorophenyl) methyl7-6- methyl, 4,5-pyrimidinediamine (interm. 9).

In a similar manner the following compound was prepared: 6-chloro-N4- (2,4-dimethylphenyl) methyl] -4,5-pyridininediamine (interm. 10).

Example 2 To a mixture of 4,5-pyrimidinediamine (20.2 parts), pyridine (40 parts) and N, N-dimethylformamide (144 parts) was added dropwise at 10 ° C dropwise 4-fluorobenzoyl chloride (24.2 parts). ) solution in N, N-dimethylformamide 25 (36 parts). After the addition was complete, stirring was continued for 30 minutes at room temperature. 600 parts of water were added. :. . The product was filtered off and dried, yielding 30 parts (70%) of N- (4-amino-5-pyrimidinyl) -4-fluorobenzamide (interm. 11).

To a mixture of N- (4-amino-5-pyrimidinyl) -4-fluorobenzamide (30 parts) and tetrahydrofuran (360 parts) was added portionwise 9.86 parts of lithium tetrahydroaluminate with stirring under nitrogen. The mixture was stirred for 6 hours. A second portion of lithium tetrahydroaluminate (10 parts) was added portionwise to the sit-r 'and stirring was continued at room temperature for 2 hours. The reaction mixture was quenched with water.

i 5 7 O 4 31

The layers were separated. The aqueous phase was extracted with tetrahydrofuran. The combined organic phases were dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 18 parts (63.5%) of N5- (74-fluorophenyl) methyl--4,5-pyrimidinediamine (interm. 12).

Following the same procedure and using equivalent amounts of the appropriate starting materials, the following compounds were also prepared: N- (4-amino-6-hydroxy-5-pyrimidinyl) -4-fluorobenzamide (interm. 13); and 6-amino-5- (774-fluorophenyl) methyl / amino] -4-pyrimidinol (interm. 14).

Example 3 6-Chloro-N- (2-pyridinylmethyl) -4,5-pyrimidinediamine (62.2 parts), a 4% methanol solution of thiophene (3 parts), calcium oxide (20 parts) and methanol (3 parts). 400 parts) the mixture was hydrogenated at normal pressure at 50 ° C using 10% Pd / C catalyst as catalyst. After uptake of the calculated amount of hydrogen, the catalyst was filtered off and the filtrate was evaporated, yielding 63.5 parts (100%) of N4 - (- pyridinylmethyl) -4,5-pyrimidinediamine as a residue (interm. 15).

In a similar manner the following compounds were also prepared: N - (- 774-fluorophenyl) methyl-4,5-pyrimidinediamine (interm. 16); N- (2-furanylmethyl) -4,5-pyrimidinediamine, m.p. 116.4 ° C (interm. 17); N- (2-thienylmethyl) -4,5-pyrimidinediamine (interm. 18); N - [(75-methyl-2-furanyl) methyl] -4,5-pyrimidinediamine (interm. 19) N - ((2-pyrazinylmethyl) -4,5-pyrimidinediamine (interm. 20); 35 N - [(4-methoxyphenyl) methyl] -4,5-pyrimidinediamine (interm. 21); 32 13/04 N4- (4-thiazolylmethyl) -4,5-pyrimidinediamine (interm. 22).

By the same procedure the following compound was also prepared: N, N - ((2,4-dimethylphenyl) methyl] -4,5-pyridinediamine (interm. 23).

Example 4 A mixture of N4- (T4-fluorophenyl) methyl-4,5-pyrimidinediamine (8.72 parts), carbon disulfide (63 parts) and N, N-dimethyl-formamide (45 parts) was stirred at reflux for 3 hours. . The cooled mixture was poured into water. The precipitated product was filtered off and dried, yielding 10.1 parts (78.9%) of 9- (74-fluorophenyl) methyl-9H-purine-8-thiol (interm. 24).

To a solution of potassium hydroxide (4.6 parts) in water (200 parts) was added portionwise 1.7 parts of iodomethane and then dropwise 3.8 parts of 9- (74-fluorophenyl) methyl-7-9H-purine t-thiol. After the addition was complete, the mixture was stirred for 2 hours at room temperature. The precipitated product was filtered off and dried, yielding 3.45 parts (73.9%) of 9- [7-fluorophenyl) methyl] -8- (methylthio) -9H-purine, m.p. 167.1 ° C (interm. 25).

Example 5

A mixture of methyl 3-methyl-4-oxo-1-piperidinecarboxylate (26 parts), benzenemethanamine (16.5 parts), a 4% ethanolic solution of thiophene (2 parts) and methanol (200 parts) was hydrogenated under normal pressure at room temperature. temperature using a 10% palladium / carbon catalyst (3 parts).

After uptake of the calculated amount of hydrogen, the catalyst was filtered off and the filtrate was evaporated to dryness, yielding 40.2 parts of methyl 3-methyl-4- (7-phenylmethyl) -amino-7-piperidinecarboxylate (interm. 26).

40 parts of methyl 3-methyl-4- (7-phenylmethyl) amino] -1-piperidinecarboxylate and 160 parts of methanol were hydrogenated at 35 under normal pressure at room temperature using a 10% palladium / carbon catalyst (2 parts). After the calculated amount of 33 i · 2 '·' a 4 hydrogen was bound, the catalyst was filtered off and the filtrate was evaporated to dryness. The residue was distilled (b.p. 80 ° C 0.1 mm pressure). The distillate was further purified by gas chromatography (215 ° C 68.9 kPa), yielding 8.6 parts of methyl 4-amino-5-no-3-methyl-1-piperidinecarboxylate (interm. 27).

To a stirred and cooled (~ 10 ° C) mixture of carbon disulfide (138.6 parts), Ν, Ν'-methanetrayl-bis / cyclohexanamine7 (138.6 parts) and tetrahydrofuran (450 parts) was added dropwise 106 parts at -10 ° C. 4-amino-3-methyl-1-10 piperidinecarboxylate. The reaction mixture was allowed to warm to room temperature. After stirring for 1 hour at room temperature, the mixture was evaporated and the residue was stirred in 2,2'-oxybispropane. The precipitate was filtered off and the filtrate was evaporated, yielding 141.1 parts (100%) of methyl cis-4-isothiocyanato-3-methyl-1-piperidinedicarboxylate (interm. 28).

Following the same procedure and using equivalent amounts of the appropriate starting materials, the following compounds were also prepared: methyl (cis + trans) methyl 4-amino-3-methyl-1-piperidinecarboxylate: b.p. 136-140 ° C (water pump) (interm. 29); and methyl (cis + trans) -4-isothiocyanato-3-methyl-1-piperidinecarboxylate (interm. 30).

25 Example 6. ... A mixture of N4- (2-furanylmethyl) -4,5-pyrimidinediamine (42.5 parts), ethyl 4-isothiocyanate-1-piperidinecarboxylate (50.5 parts) and tetrahydrofuran (630 parts) was stirred at reflux for 48 hours. After cooling, the product was filtered, washed with tetrahydrofuran and 1,1'-oxybisethane and dried to give 86.4 parts (96.2%) of ethyl 4 - [(774- (2) -furanylmethyl) amino] -5-pyrimidinyl-7-amino-thioxomethyl-17-amino-7-piperidinecarboxylate (interm. 31).

y, O 4 34

In a similar manner the following compounds were also prepared: r2 * 1 C / s HtVA ^ A2 r \. »1 '3 f 2 T Ϊ 2 3 4

No. L R R -A = A -A = A - isomer m.p.

^ form ° C

32 C2H5OCO-H4-F-C6H4-CH2 ~ -N = CN = C ~ 33 C2H5OCO-H 2 -thionyl; u-CH2- -N = CN = C- 34 C "HcOCO-H 2-Pyridir CH-- -N = CN = C- 2 5 έ 35 C6H5CH2- H4-F-C6H4-CH2 ~ -C = NC = N- - ~ | 15 36 C „HcOCO-H (5-CH.-2-furanyl) - -N = CN = C ~ 2 5 3 ch2- 37 C„ HcOCO-H 2T? 5 li 38 CH_OCO_ 3-CH, 4-FC H -CH - -N = CN * C- cis 3 3 oh Δ 39 CH 0CO-3-CH »4-FC.H -CH - -N = C ~ N = C- cis + trans -

3 3 O 4 Z

40 CH-OCO- H 4-CH, O-C, H.-CH - -N = C ~ N = C- 20 2 5 o 6 4 2 41 CH OCO- H 4-thiazoyl — CH - -N = CN = C- 2 5_li 2_

The following compounds were also prepared in a similar manner: 4- (4-Amino-6-hydroxy-5-pyrimidinyl-N- [7-fluorophenyl] methyl) -N '- [7- (phenylmethyl) -4-piperidinyl] thiourea , sp. 192.9 ° C (interm. 42): and ethyl 4- (774-amino-6-hydroxy-5-pyrimidinyl) - (7,4-fluorophenyl) methyl] amino] thioxomethyl] amine-1-piperidine-30 carboxylate (interm. 43).

In a similar manner the following compound was prepared: ethyl 4- (7- [4- (772,4-dimethylphenyl) methyl] amine] -5-pyrimidinyl] aminothioxomethyl7amino] -1-piperidinecarboxylate (interm. 44).

Tue 7 04 35

Example 7 A mixture of 1- (phenylmethyl) -4-piperidineacetic acid hydrochloride (52.4 parts), N4- / T4-fluorophenyl) methyl--4,5-pyrimidinediamine (38.7 parts) and phosphoryl chloride (765 parts) stirred and refluxed for 30 minutes. The reaction mixture was evaporated. The residue was decomposed with ice water. Sodium hydroxide was added and the product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by chromatography on a Kro-10 column of silica gel, eluting with a mixture of trichloromethane and methanol saturated with ammonia (95: 5 by volume). The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile.

The product was filtered off and dried, yielding 37 parts (61%) of N- (4- (4,774-fluorophenyl) methyl] methyl] amino-5-pyrimidinyl] -1- (phenylmethyl) -4-piperidineacetamide, m.p. 157.3 ° C (interm. 45).

Example 8

To a stirred mixture of isocyanatoethane (14.2 parts), sodium azide 20 (29.2 parts) and anhydrous tetrahydrofuran (135 parts) was added a solution of aluminum chloride (39 parts) in anhydrous tetrahydrofuran (225 parts). Stirring was continued overnight at reflux temperature. The reaction mixture was cooled and acidified with 6 M HCl-25 solution. The mixture was evaporated to dryness and the product was extracted 4 times with 2-propanone. The combined extracts were dried, filtered and evaporated. The residue was dried overnight, yielding 18 parts (65%) of 1-ethyl-1,4-dihydro-5H-terrazol-5-one (interm. 46).

To a solution of 1,2-dibromoethane (109 parts) and sodium carbonate (21.2 parts) in a mixture of water (5 parts) and N, N-dimethylformamide (18 parts) was added dropwise at about 40 ° C dropwise 1-ethyl A solution of 1,4-dihydro-5H-tetrazol-5-one (22.5 parts) in a mixture of water (5 parts) and N, N-dimethylformamide-35 (27 parts). After the addition was complete, stirring was continued overnight at 40 ° C. The organic phase was separated, dried and distilled to give 9.8 parts (22%) of 1- (2-bromoethyl) -4-ethyl-1,4-dihydro-5H-tetrazol-5-one, b.p. 110 ° C / 0.1 mm (interm. 47).

Example 9 A mixture of 2-thiazolamine (50 parts), 3-acetyl-4,5-dihydro-2- (3H) -furanone (76 parts), concentrated hydrochloric acid (1.2 parts) and methylbenzene (270 parts) was stirred and boiled at reflux for 2 hours using a water separator. The reaction mixture was cooled and 340 parts of phosphoryl chloride were added at 20-30 ° C. The mixture was slowly heated to 100-110 ° C and stirring at this temperature was continued for 2 hours. The reaction mixture was evaporated and the residue was poured into a mixture of ice and ammonium hydroxide. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanol and 1,1'-oxybisethane, yielding 36 parts of 6- (2-chloroethyl) -7-methyl-5H-thiazolo [3,2-a] pyrimidin-5-one (interm. 48).

B. Manufacture of finished products

Example 10 A mixture of 1- (phenylmethyl) -4-piperidineacetic acid hydrochloride (20.65 parts) 6-chloro-N4- (T4-fluorophenyl) methyl-4,5-pyrimidinediamine (19.5 parts) and phosphoryl chloride (510 parts) stirred and heated to reflux for 13 hours. The reaction mixture was evaporated. The residue was poured into ice water. The mixture was treated with sodium hydroxy-30. The product was extracted with 4-methyl-2-pentanone. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol saturated with ammonia (97: 3, v / v) as eluent. The first 35 fractions were collected and the eluent was evaporated, yielding 23.6 parts (75%) of 6-chloro-η 5 7 O- [4- (4-fluorophenyl) methyl] -8- [T- (phenylmethyl) as an oily residue. ) -4-piperidinyl-7-methyl-9H-purine (Compound 1).

In a similar manner the following compounds were also prepared: 6-chloro-7- ([4-fluorophenyl) methyl] -8- [N- (phenylmethyl-5H) -4-piperidinyl] methyl] -7H-purine (Compound 2); and 9- (74-fluorophenyl) methyl-6-6-methyl-8- [1- (phenylmethyl) -4-piperidinyl] methyl] -9H-purine, oil (Compound 3).

Example 11 A mixture of N- (4- (774-fluorophenyl) methyl] amino] -5-pyrimidin-10-yl] -1- (phenylmethyl) -4-piperidineacetamide (36 parts) and phosphoryl chloride (935 parts) was stirred and refluxed for 8 hours. The mixture was allowed to cool, then evaporated to dryness. The residue was decomposed in ice water. The mixture was treated with sodium hydroxide solution.

The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by K-chromatography on a silica gel column using a mixture of trichloromethane and methanol saturated with ammonia (97: 3, v / v) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in 2,2'-oxybibpropane. The product was filtered and crystallized from acetonitrile. The product was filtered off and dried, yielding 10.6 parts (30.4% of 9- [7,4-fluorophenyl) methyl] -8- [7- (phenylmethyl-4-piperidinyl) methyl] -9H-purine, mp 136.4 ° C. (compound 4).

Example 12 A mixture of 1- (phenylmethyl) -4-piperidinol (12.6 parts), a 50% dispersion of sodium hydride (3.2 parts) and N, N-dimethylacetamide (200 parts) was stirred at room temperature. for an hour. To the mixture was added portionwise 18 parts of 9- (7-fluorophenyl) methyl-7- (methylthio) -9H-purine, and after the addition was complete, the mixture was stirred for another 4 hours at room temperature. The reaction mixture was poured into water. The product was filtered and dissolved in trichloromethane. The organic layer was washed with water and filtered through diatomaceous earth. The filtrate was dried, filtered and evaporated. The product was crystallized from acetonitrile, filtered and dried to give 16.75 parts (61.1%) of 9- (7,4-fluorophenyl) methyl-7-8- [N- (phenylmethyl) -4-piperidinyl] oxy] -9H-purine, i. 117.0 ° C (comp. 5).

Example 13 To a mixture of 9- (74-fluorophenyl) methyl] -9H-purine-8-thiol (13 parts) and water (300 parts) was added 2 parts of sodium hydroxide with stirring. The reaction mixture was filtered through diatomaceous earth. The filtrate was evaporated, the residue was dissolved in methyl benzene and the solvent was evaporated again (this was repeated twice). The residue was dissolved in 270 parts of Ν, Ν-dimethylacetamide, and 19.3 parts of 1- (74-methylphenyl) sulfonyl] -4-piperidinolmethanesulfonate (ester) were added to the solution. The mixture was stirred over the weekend at 60 ° C. The reaction mixture was poured into water, and the product was extracted with 4-methyl-2-pentanone. The extract was washed with water, dried, filtered and evaporated, yielding 27 parts (100%) of 4- (79- (T4-fluorophenyl) methyl] -9H-purin-8-yl] -1- (74-methylphenyl) sulfonyl] piperidine (compound 6). ).

Example 14

A mixture of ethyl 4 - [((2- (4-furanylmethyl) amino) -5-pyrimidinyl) amino] thioxomethyl] amino] -1-piperidinecarboxylate (4 parts), mercuric oxide (6 parts) and ethanol (80 parts) was stirred. 2 hours at reflux temperature. The mixture was filtered through Hyflo04 hot and the filtrate was evaporated. The residue was crystallized from a mixture of acetonitrile and ethanol. The product was filtered off and dried, yielding 0.8 parts (21.5%) of ethyl 4- [9- (2-furanyl-3-methyl) -9H-purin-8-yl] amino] -1-piperidinecarboxylate, m.p. 171.9 ° C (comp. 7).

Following the same procedure and using equivalent amounts of the appropriate starting materials, the following compound was also prepared: 39 1-: 3 --- 0 4

Example 15

Ethyl 4 - [(4 - [(7-phenylmethyl) amino] -5-pyrimidinyl] amino] thioxomethyl] amino] -1-piperidinecarboxylate (24 parts), mercuric oxide (24 parts) and ammonia-5α saturated methanol (240 parts) ) the mixture was stirred and refluxed overnight. The reaction mixture was filtered hot and the filtrate was evaporated. The residue was dissolved in a mixture of trichloromethane and ethanol. The organic layer was washed with water and evaporated and the residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 20.3 parts (92.1%) of ethyl 4- [9- (phenylmethyl) -9H-purin-8-yl] amino] -1-piperidinecarboxylate, m.p. 156.9 ° C (comp. 9).

In a similar manner the following compounds were also prepared: ethyl 4- [9- (2-thienylmethyl) -9H-purin-8-yl] amino] -1-piperidinecarboxylate (Compound 10); Ethyl 4- [9- (2-pyridinylmethyl) -9H-purin-8-yl] amino] -1-piperidinecarboxylate (Compound 11); Ethyl 4- [9 - [(5-methyl-2-furanyl) methyl] -9H-purin-8-yl] amino] -1-piperidinecarboxylate (Compound 12); Ethyl 4- [9- (2- pyrazinylmethyl) -9H-purin-8-yl-amino-1,1-piperidinecarboxylate (Compound 13); ethyl 4- [9-methyl-9H-purin-8-yl) -amino] -1-piperidine-25-carboxylate, mp 169.6 ° C (Compound 14), ethyl 4- [29 - [(4-methoxyphenyl) methyl] -9H-purin-8-yl] amino] -1-1-piperidinecarboxylate, mp 168.1 ° C (Compound 15), and N N- (phenylmethyl) -4-piperidinyl] 79H-purin-8-amine, mp 276.1 ° C (comp. 16).

Example 16

Ethyl 4- [77 / 4- (cyclopropylamino) -5-pyrimidinyl] amino] thioxomethyl7amino] -1-piperidinecarboxylate (15.7 parts), mercuric oxide (20 parts), ethanol 35 (40 parts) and N, N -dimethylacetamide (135 parts) was stirred overnight at 80 ° C. The reaction mixture was filtered hot through diatomaceous earth. The filtrate was poured into water and the product was extracted with dichloromethane. The organic layer was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.2 parts (14.1%) of ethyl 4- (79-cyclopropyl-9H-purin-8-yl) amino] -1-piperidinecarboxylate, m.p. 177.0 ° C (comp. 17).

In a similar manner the following compound was prepared: Ethyl 4- [9- (4-thiazolylmethyl) -9H-purin-8-yl] amino] -1-piperidinecarboxylate (Compound 18).

Example 17

Methyl (cis-4- (7774- (24-fluorophenyl) methyl) amino] -5-pyrimidinyl] amino] thioxomethyl7amino-3-methyl-1-pi-15 peridinecarboxylate (13 parts), mercuric (II) oxide (13 parts), sulfur (0.1 parts) parts) and a mixture of ammonia-saturated methanol (160 parts) was stirred at reflux for 0.5 hours. The reaction mixture was filtered hot through diatomaceous earth and the filtrate was evaporated. The residue was poured into water and the product was extracted with trichloromethane.

The extract was washed with water, dried, filtered and evaporated. The residue became solid in 1,1'-oxybisethane. The product was filtered off and dried, yielding 7 parts (58.5%) of methyl cis-4- [79 - [(4-fluorophenyl) methyl] -9H-25-purin-8-yl] amino] -3-methyl-1-piperidinecarboxylate, mp 152.2 ° C (comp. 19).

In a similar manner the following compounds were also prepared: 7- (7-fluorophenyl) methyl-N- [1- (phenylmethyl) -4-piperidinyl] -7H-purin-8-amine, m.p. 251.1 ° C (comp. 20).

Methyl (cis + trans) -4- (79- [74-fluorophenyl) methyl] -9H-purin-8-yl-amino-3-methyl-1-piperidinecarboxylate (Compound 21).

In a similar manner the following compounds were also prepared: ethyl 4- [9- (74-fluorophenyl) methyl] -9H-purin-8-yl] -35-methylamino-1-piperidinecarboxylate (Compound 22); and £ 370,441 ethyl 4- (79- [72/4-dimethylphenyl) methyl] -9H-purin-8-yl] amino] -1-piperidinecarboxylate (Compound 23).

Example 18

Ethyl 4 - [((7-amino-6-hydroxy-5-pyrimidinyl) 5 (74-fluorophenyl) methyl] amino] thioxomethyl] amino] -1-piperidinecarboxylate (88.8 parts), mercuric (II) oxide (88 parts), sulfur (0 , 1 part) and ethanol (1200 parts) were stirred at reflux overnight. The reaction mixture was filtered hot through diatomaceous earth and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol saturated with ammonia (95: 5, v / v) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from ethyl acetate. The product 15 was filtered off and dried, yielding 50.7 parts (66.1%) of ethyl-4- (7-amino-1- [7,4-fluorophenyl) methyl] oxazolo [5,4-d] pyrimidin-2 (1H) - ylideneamino-7-piperidinecarboxylate, m.p. 174.6 ° C (comp. 24).

Ethyl 4- (7-amino-1- (7,4-fluorophenyl) methyl] -20-oxazolo [5,4-d] pyrimidin-2 (1H) -ylidene] amino] -1-piperidinecarboxylate (50.7 parts), and phosphoryl chloride ( 3050 parts) the mixture was stirred at reflux for 90 minutes. The reaction mixture was evaporated. The residue was poured into ice water. The mixture was treated with ammonium hydroxy-25. The product was extracted with 4-methyl-2-pentanone. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol saturated with ammonia (95: 5 by volume) as eluent.

The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 21.6 parts (41.5%) of ethyl 4- (6-chloro-7- [7-fluorophenyl) methyl] -7H-purin-8-yl] -amino] -1-piperidinecarboxylate, mp. 126.6 ° C (comp. 25).

42 13704

Following the same procedure and using equivalent amounts of the appropriate starting materials, the following compounds were also prepared: 1- (T4-fluorophenyl) methyl] -2,3-dihydro-2 - [(N- (phenylmethyl) 5-piperidinyl] imino] oxazolo / 5.4 -d7pyrimidin-4-amine, m.p. 178.5 ° C (comp. 26); and 6-chloro-7 - [(4-fluorophenyl) methyl] -N- [N-phenylmethyl) -4-piperidinyl] -7H-purin-8-amine, mp 248.6 ° C (Compound 27 ) m 1 0 Example 19 6-Chloro-7- [4-fluorophenyl) methyl] -8- [((phenylmethyl) -4-piperidinyl] methyl] -7H-purine (16 parts), ethyl chlorocarbonate ( 4.65 parts) and a mixture of methylbenzene (180 parts) were stirred at reflux for 15 hours. The cooled mixture was treated with ammonium hydroxide and the product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated, yielding 18.7 parts (100%) of ethyl 4- (76-chloro-7- [7-fluorophenyl) methyl] -7H-purin-8-yl] methyl] -1-20 piperidinecarboxylate. (Compound 28).

In a similar manner the following compounds were prepared: ethyl 4- (9- (7β-fluorophenyl) methyl] -6-methyl-9H-purin-8-yl] methyl] -1-piperidinecarboxylate (Compound 29); and ethyl 4- (6-chloro-9- (74-fluorophenyl) methyl] -9H-purin-25-yl] methyl] -1-piperidinecarboxylate (Compound 30).

Example 20 A mixture of 4- (2 - [(4-fluorophenyl) methyl] -9H-purin-8-yl] -1- (7,4-methylphenyl) sulfonyl] piperidine (24.8 parts) and hydrogen bromide saturated acetic acid (300 parts) was stirred at room temperature. overnight. The mixture was evaporated and the residue was added to the residue. The mixture was treated with sodium hydroxide solution and then extracted with dichloromethane. The extract was acidified with hydrochloric acid solution and extracted with water. The aqueous layer was treated with sodium hydroxide solution and the product was extracted with dichloromethane. The extract was washed with water, dried, filtered and treated with water. 'o 4 was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95: 5, v / v) as eluent -> a mixture of trichloromethane and methanol saturated with ammonia (90:10, v / v). The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetone. The product was filtered off and dried, yielding 3.0 parts (17.4%) of 9 - [(4-fluorophenyl) methyl] -8- (4-piperidinylthio) -9H-purine, m.p. 113.5 ° C (comp. 31). In a similar manner the following compound was also prepared: 9 - [(4-fluorophenyl) methyl] -8- (4-piperidinylsulfonyl) -9E-purine (Compound 32).

Example 21

Ethyl 4- (79-furanylmethyl) -9H-purin-8-ylamino-15-nor-1-piperidinecarboxylate (60.5 parts), potassium hydroxide (90 parts), 2-propanol (800 parts) and water (20 parts) ) the mixture was stirred at reflux for 48 hours. The reaction mixture was evaporated. The reaction mixture was poured into water with stirring. The product was filtered off and dried, yielding the first fraction, 36.2 parts of 9- (2-furanylmethyl) -N- (4-piperidinyl) -9H-purine-8-amine hemihydrate. The aqueous phase was extracted with dichloromethane. The organic layer was dried, filtered and evaporated, the oily residue was taken up in acetonitrile and 2,2'-oxy-25 bispropane. The product was filtered off and dried, yielding another fraction, 5.6 parts of 9- (2-furanylmethyl) -N- (4-piperidinyl) -9H-purin-8-amine. The total yield was 41.8 parts (86%) of 9- (2-furanylmethyl) -N- (4-piperidinyl) -9H-purin-8-amine hemihydrate, m.p. 164.1 ° C (compound 33).

Following the same procedure and using equivalent amounts of the appropriate starting materials, the following compounds were also prepared: 9- ([4-fluorophenyl) methyl] -N- (4-piperidinyl) -9H-purine-35-n-8-amine dihydrochloride, m.p. 275.0 ° C (comp. 34); 44 tJ704 N- (4-piperidinyl) -9- (2-thienylmethyl) -9H-purin-8-amine, m.p. 189.6 ° C (comp. 35); N- (4-piperidinyl) -9- (2-pyridinylmethyl) -9H-purin-8-amine, m.p. 194.8 ° C (comp. 36); 59- (5-methyl-2-furanyl) methyl] -N- (4-piperidinyl) -9H-purin-8-amine, m.p. 165.1 ° C (comp. 37); N- (4-piperidinyl) -9- (2-pyrazinylmethyl) -9H-purin-8-amine (Compound 38); and 9- ([4-methoxyphenyl) methyl] -N- (4-piperidinyl) -9H-purine-10-amine-8-amine hemihydrate, m.p. 144.1 ° C (comp. 39).

In a similar manner the following compound was prepared: 9- (7,4,4-dimethylphenyl) methyl-N- (4-piperidinyl) -9H-purin-8-amine (Compound 40).

Example 22 Ethyl 4- (76-chloro-7- [74-fluorophenyl) methyl] -7H-purin-8-yl] amino] -1-piperidinecarboxylate (7.5 parts) and 48% aqueous HBr (150 parts) ) was stirred overnight at 80 ° C. The reaction mixture was evaporated. The residue was stirred in 2-propanone. The product was filtered off and dried, yielding 8.5 parts (100%) of 7- (7-fluorophenyl) methyl] -8- (4-piperidinylamino) -7H-purin-6-ol hydrobromide (compound 41).

In a similar manner the following compounds were also prepared: 9- (14-fluorophenyl) methyl-7-8- (4-piperidinylmethyl) -9H-25 purin-6-ol hydrobromide (Compound 42); and 7- (7-fluorophenyl) methyl-7- 8- (4-piperidinylmethyl) -7H-purin-6-ol hydrobromide, m.p. 277.8 ° C (comp. 43). Example 23

A mixture of ethyl 4- (79-methyl-9H-purin-8-yl) amino] -1-piperidinecarboxylate (10.5 parts) and 48% aqueous HBr (300 parts) was stirred at 80 ° C. at 6 hours. The mixture was evaporated and the residue was boiled in methanol. The reaction mixture was cooled and the precipitated product was filtered. The product was again boiled in methanol, the product was filtered off and dried, yielding 7.7 parts (56.6%) of 9-methyl-N- (4-piperidinyl) -9H-purine-8-amine dihydro-45 .mu.l bromide, sp. 298.3 ° C (comp. 44).

In a similar manner the following compounds were prepared: cis-9- (84-fluorophenyl) methyl-N- (3-methyl-4-piperidin-5-yl) -9H-purine-8-amine dihydrobromide (Compound 45); 9- (phenylmethyl) -N- (4-piperidinyl) -9H-purine-8-amine dihydrobromide, m.p. 270.9 ° C (comp. 46); (cis + trans) -9 - [(4-fluorophenyl) methyl] -N- (3-methyl-4-piperidinyl) -9H-purine-8-amine dihydrobromide (Compound 10 te 47); 9- ([4-fluorophenyl) methyl] -6-methyl-8- (4-piperidinyl) methyl-9H-purine (Compound 48); 9-cyclopropyl-N- (4-piperidinyl) -9H-purin-8-amine, m.p. 140.6 ° C (comp. 49); and N- (4-piperidinyl) -9- (4-thiazolylmethyl) -9H-purin-8-amine, m.p. 208.4 ° C (comp. 50).

In a similar manner the following compound was prepared: 9- (4-fluorophenyl) methyl-N-methyl-N- (4-piperidinyl) -9H-pyrin-8-amine (Compound 51).

Example 24 9 - ((14-fluorophenyl) methyl] -8- [7H- (phenylmethyl) -4-piperidinyl] methyl-9H-purine (17.6 parts), methanol (200 parts) and 10% Pd / C- the catalyst mixture (2 parts) was hydrogenated under normal pressure at room temperature. After uptake of the calculated amount of hydrogen, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was converted to the ethanedioate salt in ethanol. The salt was filtered off and dried, yielding 8.1 parts (38.1%) of 9 - [(4-fluorophenyl) methyl] -8- (4-piperidinylmethyl) -9H-purine ethanedioate (1: 2), m.p. 163.9 ° C (comp. 52).

In a similar manner the following compounds were also prepared: 7- (4-fluorophenyl) methyl 7 '- N- (4-piperidinyl) -N-7H-purin-35-n-8-amine (Compound 53); and 46 i (37- (14-fluorophenyl) methyl] -6-methoxy-8- (4-piperidinylmethyl) -9H-purine (Compound 54).

Example 25 6-Chloro-7- (7,4-fluorophenyl) methyl-7- (N - (T-phenyl-5-methyl) -4-piperidinyl] -7H-purine (15 parts), calcium oxide (5 parts) in methanol (200 parts) ) and a mixture of 10% Pd / C catalyst (2 parts) was hydrogenated at room temperature under normal pressure. After the calculated amount of hydrogen was bound, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using mixtures of trichloromethane and methanol saturated with ammonia (95: 5 → 85: 5, 15 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 5.8 parts (54%) of 7- [14-fluorophenyl) methyl] -8- (4-piperidinylmethyl) -7H-purine (compound 55).

Example 26 9- (14-fluorophenyl) methyl-7- [N- (phenylmethyl) -4-piperidinyl] oxy] -9H-purine (16.25 parts), methanol (200 parts), 10% Pd / C- a mixture of catalyst (3 parts) and Raney nickel (6 parts) was hydrogenated at normal pressure at 50 ° C. After the calculated amount of hydrogen was bound, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in trichloromethane, and water was added to the solution. The product was extracted with trichloromethane. The extract was washed; with water, dried, filtered and evaporated. The residue was stirred in 1,1'-oxybisethane. The precipitated product 30 was filtered off and dried, yielding 10.5 parts. (82.2%) 9- (74-fluorophenyl) methyl] -8- (4-piperidinyloxy) -9H-purine, m.p. 79.3 ° C (comp. 56).

• · · 47 15/04

Example 27 2,3-Dihydro-1,4-benzodioxine-2-methoxy-4-methyl-benzenesulfonate (ester) (3.2 parts), 9 - [(4-fluorophenyl) methyl] -8- (4- a mixture of piperidinylmethyl) -9H-purine-6-5 ol hydrobromide (5 parts), sodium carbonate (3 parts) and N, N-dimethylacetamide (45 parts) was stirred overnight at 70 ° C. The cooled reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol saturated with ammonia (90:10, v / v) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized twice: first from acetonitrile and then from ethanol. The product was filtered off and dried, yielding 0.8 parts (16.3%) of 8 - [[7- (7,3,3-dihydro-1,4-benzodioxin-2-yl) methyl] -4-piperidinyl] methyl] - (74-fluorophenyl) methyl-9H-purin-6-ol, m.p. 200.7 ° C (comp. 57).

In a similar manner there was also prepared the following compound: 8- [77 - [(2,3-dihydro-1,4-benzodioxin-2-yl) methyl] -4-20 piperidinyl] amino-7-7- (7-fluorophenyl) methyl] -7H -purin-6-ol, m.p. 257.5 ° (comp. 58).

Example 28 2,3-Dihydro-1,4-benzodioxine-2-methanol-4-methyl-benzenesulfonate (Ester) (3.2 parts), 7- (7-fluorophenyl) methyl 7-8- (4-pioidinylmethyl) -7H -purin-6-olihydro-:. a mixture of bromide (4.5 parts), sodium carbonate (4 parts) and N, N-dimethylformamide (45 parts) was stirred overnight at 70 ° C. The cooled mixture was filtered through diatomaceous earth and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol saturated with ammonia (95: 5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile.

The product was filtered to give 1.5 parts (34%) of 48 13 7 04 8 - (N- (2,3-dihydro-1,4-benzodioxin-2-yl) methyl) -4-piperidinyl] methyl7- 7- (4-fluorophenyl) methyl-7H-purin-6-ol, m.p. 175.2 ° C (comp. 59).

In a similar manner the following compounds were prepared: N- (N- (2,3-dihydro-1,4-benzodioxin-2-yl) methyl) -4-piperidinyl-7- (2-furanylmethyl) -9H-purine- 8-amine dihydrochloride dihydrate, m.p. 174.4 ° C (comp. 60); and N- (T- (2,3-dihydro-1,4-benzodioxin-2-yl) methyl) -4- (10-piperidinyl) -5- [(5-methyl-2-furanyl) methyl] -9H-purine- 8-amine, m.p. 200.8 ° C (comp. 61)

Example 29 1- (2-Chloroethyl) -4-methoxybenzene (1.9 parts), 7- (14-fluorophenyl) methyl] -8- (4-piperidinylmethyl) -157H-purin-6-ol hydrobromide (5 parts), a mixture of sodium carbonate (4 parts) and N, N-dimethylacetamide (45 parts) was stirred overnight at 70 ° C. The cooled reaction mixture was filtered through diatomaceous earth and the filtrate was evaporated. The residue was purified by chromatography on a column of silica gel using a mixture of trichloromethane and methanol saturated with ammonia (95: 5, v / v) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.2 parts (46%) of 7- (4-fluorophenyl) methyl] -8- [N- [2- (4-methoxyphenyl) ethyl] -4-piperidinyl] methyl] 77-purine. 6-olia, m.p. 122.2 ° C (comp. 62).

The following compounds were also prepared in a similar manner: 30. 35 49 ί 3 7 0 4 2 1 12 3 4 No. L R B R ~ A = A -A = A - isom.

form * - 63 4-CH 0 -C C -C -C H - H CH. 4-F "C, H -CH - -N = CN = C (OH) - - 197.0 36426 2 642 '64 4-CH 0-CH -CH," HO 4-FC.H -CH - -N = CN = C- - 120.0 36425 642 '5 65 4-CH OC H -CH- CH NH 4-FC, H.- CH - -N = CN = C- cis 160.5 364253 642 66 4 ~ CH 0 ~ CH -C-Η - H NH CH - -N = CN = C ~ - 136.5 ^ 3 6 4 2 5 3 67 4-CH_O-C, H -CH_- H NH 4-FC.H -CH - -C = NC = N- - 216.0 3 6 4 2 6 4 2 1 68 4-CH-OC, H -C_Hc- H NH cyclopropylj -N = CN = C- - 166.1 OO 4 Δ Ό 69 4-CH OC H-CHg-H NH 4-thiazyl-CH2- -N = C ~ N = C- - 152.2 10 70 4-CH_O-CH -C_H - H NH 4-CH_O-C, H-CH ,, - N = CN = C- - 167.8 36425 3642 '71 4-CH.O-CH.-CH, - HS 4-FC.H -CH - -N = C ~ N = C- - 102 In the same manner, the following compounds were also prepared: 9- (14-fluorophenyl) methyl] -8- [1- [2- (2-methoxyphenyl) ethyl] -4-piperidinyl] ethyl-9H -purine (Compound 72); 9- ((4 - fluorophenyl) methyl] -N-methyl-N- [1- [2- (4-methoxy-20-phenyl) ethyl] -7H-piperidinyl] -9H-pyrene ini-8-amine (Compound 73).

Example 30. , 1- (2-chloromethyl) -4-methoxybenzene (2 parts) N- (4-piperidinyl) -9- (2-pyridinylmethyl) -9H-purine-25-amine (3.1 parts), sodium carbonate (1 part) , 5 parts) and a mixture of N, N-dimethylformamide (45 parts) were stirred overnight at 70 ° C. The reaction mixture was poured into water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by chromatography on a column of silica gel using a mixture of trichloromethane and methanol saturated with ammonia (95: 5, v / v) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2.2 parts (50%) of Ν- [Ϊ- / 2- (4-methoxyphenyl) ethyl] -4-piperi- ε 3 704 50 dinyl7-9- (2-pyridinylmethyl) -9H -purin-8-amine, m.p. 144.5 ° C (comp. 74).

5 Rl i

™ 3 ° - (3'cvcv, 0 'ni'N!

W \ _V H N- ^ 4/10 inro H1 -a3 = A2-A3 = A4- Base or salt m.p.

shape ° C

75 4-F-C6H4-CH2 ~ -N = C-N = C- base 170; 6 76 2-fura "-CH- -N = C ~ N = C- base 140.6 nyl 2 ,,,.

77 2-thienyl-CH2- -N = CN = C- hemihydrate 135.9 15 78 4-F-C6H4 ~ CH2- -C = NC = N-base 194.9 79 5-CH3-2-furatyl-CH2 N = C ~ N = C- base 164.9 BO 4-FC..H -CH-- -N = CN = C- (E) -2-butenedioate- 156.2 6 4 2 11 (2: J) B1 4-F-C6H4-CH2 ~ -C = NC = N-base 139.1 B2 4-FC H -CH, "-C (OH) = N ~ C = N-" onohydrate 222.4 6 4 2 20 B3 C6H5-CH2- -N = CN = C- base 161.5 34 4-FC, H.-CH_- -N = CN = C (CH_) - <E) "2-butylate" 148.0 * 642 In the same manner, the following compound was prepared: ethyl [2- [4- [9- (2-thienylmethyl) -9H-purin-8-yl] amino] -1-piperidinyl] ethyl] carbamate (Compound 85).

: In a similar manner the following compound was also prepared: 9- ((4-fluorophenyl) methyl] -8- [4- [2- (4-methoxyphenyl) -30 ethyl] -4-piperidinyl] sulfonyl] -9H-purine- (E) -2-bu -tenidate (1: 2) (Compound 86).

Example 31 • 3- (2-chloroethyl) -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one (1.45 parts), N- (4-piperidinyl) -9- (2- A mixture of pyraz- (35-sinylmethyl) -9H-purin-8-amine (2 parts), sodium 51 → 04 carbonate (1 part) and N, N-dimethylacetamide (45 parts) was stirred and heated at 90 ° C. overnight. The reaction mixture was poured into water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified by chromatography on a column of silica gel using a mixture of trichloromethane and methanol saturated with ammonia (95: 5, v / v) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 0.9 parts (31.6%) of 2-methyl-3- [2- [4- [9- (2-pyrazinylmethyl) -9H-purin-8-yl] amino ]- 1-piperidinyl] ethyl7-4H-pyrido, [1,2-a] pyrimidin-4-one, m.p. 180.1 ° C (comp. 87).

52 i :; o 4 R2 1 '*' "TTSs

0 N — K ** J

5 I I 2 12 3 4 No. B R R -A = A -A = A - Base or cond.

lamoform 88> 88 NH 2 -furyl-CH 2 -H-N = CN = C- H 2 O 176.6 89 NH 2-ΐίεηγγ1ί- (ΓΗ2- H -N = CN = C- base 194.3 10 90 NH 2-Puridinylic H 2 - H -N = C ~ N = C- base 201.3 91 NH 5-CH -2- [uranyl] H -N = CN = C- base 208.1

CV

92 CH_ 4-F-C, H -CH - H -N = C ~ N = C- (E) -2-butenedi- 180.0

2 D 4 2, -, r- V

oate (2.0) 93 NH 4-FC H -CH - H -C = N ~ C = N-base 211.5 15 642 '94 CH 4-FC, H -CH - H -C = N ~ C = N-' 3HCl .2H „0 217.5 2 6 4 2 2 '95 CH? 4 F-Cl 2 -CH - H ~ N = C ~ N = C (OH) - 1/21 ^ 0 196.5 96 NH 4-FC ^ H -CH - H -C (OH) = NC = N ~ HJD 201.9 6 4 2 2 is 97 CH 4-FC.H.-CH - H -C (OH) = NC = N-base 210.1 2 6 4 2 r 98 O 4-F-C & H4-CH2- H -N = CN = C- base 152.4 99 NH CH3 "H -N = CN = C- 1/2 H ^ 213.0 100 NH C6H5 ~ CH2_ H -N = CN = C- base 239.2 25 101 NH 4 -F-C6H4-CH2-3-CH3 -N = CN = C- base / cis + trans 212.5 102 NH4-F-C6H4-CH2- H -N = CN = C (CH3) - base 148.9 103 NH 4-thiazoyl-CH2-H -N = CN = C- base 222f0 53> 3 "O 4

In a similar manner the following compounds were also prepared: C 6 H 2 -Ch 2 - ^ - b ^ Y ^ 32 10 I-: - ~ \ 2 3 4 ~] iro B R 1 Ά = A -ft = A - Base "or \ p · gola form ^ 104 NH 2 -furanyl-CH 2 "-N = CN = C- base 181.6 105 NH 2 -thienyl-CH 2 ~ -N = CN = C ~ H 2 O 168.2 15 106 NH 2 -Pyrid" p CH 2 '-N = CN = C- H 2 O 164.7 107 NH 5-CH -2-furanyl - CH - -N = C ~ N = C- base 173.4 3 lx z___

In a similar manner the following compounds were also prepared: 3- (2- (4- (7 ') - [7-fluorophenyl) methyl] -6-hydroxy-9H-purin-8-yl] ethyl] -1-piperidinyl] ethyl -6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one, m.p. 171.1 ° C (comp. 108); 25 1- (3- (4- [9- (7-fluorophenyl) methyl] -6-methoxy-9H-purin-8-yl) methyl) -1-piperidinylpropyl) -1,3-dihydro-2H-benzimidazole -2-one (E) -2-butenedioate (2: 3), m.p.

179.9 ° C (comp. 109); 9- (74-fluorophenyl) methyl] -N- [7- [2- (4-morpholinyl) -

30 ethyl / -4-piperidinyl] -9H-purin-8-amine, m.p. 176.8 ° C

(compound 110); 7-methyl-6- [2- [4- [9- (2-thienylmethyl) -9H-purin-8-yl] amino] -1-piperidinyl] ethyl] -5H-thiazolo [3,2-a] pyrimidin-5-one hemihydrate; mp. 104.5 ° C (comp. 111); 35 1-Ethyl-4- (2- [4- (9- [7-fluorophenyl) methyl] -7H-purin-8-yl] -amino] -1-piperidinyl-ethyl] -4,4-dihydro-5H-tetrazole-5- oni, sp. 160.3 ° C (comp. 112); and 54 13704 3- (2- [4- (79- (74-fluorophenyl) methyl] -9H-purin-8-yl) -amino] -1-piperidinyl] ethyl] -2,4- (1H, 3H) -quinazolinedione, m.p. 241.0 ° C (comp. 113).

Example 32 3 1- (3-Chloropropyl) -1,3-dihydro-2H-benzimidazol-2-one (1.8 parts), 9- [4-fluorophenyl) methyl] -8- (4-piperidinylmethyl) - A mixture of 9H-purine (2.7 parts), sodium carbonate (1 part) and N, N-dimethylformamide (45 parts) was stirred and heated at 70 overnight. The cooled reaction mixture was poured into water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated.

The residue was purified by chromatography on a column of silica gel, eluting with a mixture of trichloromethane and methanol saturated with ammonia (95: 5, v / v).

15

The pure fractions were collected and the eluent was evaporated.

The residue was converted into the salt of (E) -2-butenedioic acid in ethanol. The salt was filtered off and dried, yielding 2.85 parts (45.9%) of 1- [3- [4- [9- [7-fluorophenyl] methyl] -7H-purin-8-yl] methyl] 1-piperidinyl] pipopyl] -1,3-20-dihydro-2H-benzimidazol-2-one (E) -2-butenedioate (1: 2), m.p. 186.2 ° C (comp. 114).

In a similar manner the following compounds were also prepared: 1- (2- (4- [9- (4-fluorophenyl) methyl] -9H-purin-8-yl) -25- [_- ”amino] -1-piperidinyl / ethyl -1,3-dihydro-2H-benzimidazol-2-one, m.p. 242.4 ° C (comp. 115); 1- (3- (4- [9- (7β-fluorophenyl) methyl] -6-hydroxy-9H-purin-8-yl) methyl] -1-piperidinyl] pipopyl] -1,3-dihydro-2H-benzimidazol-2-one , sp. 245.8 ° C (comp. 116).

In a similar manner the following compounds were prepared: 3,7-dimethyl-6- [2- (4- (79- (74-fluorophenyl) methyl] -9H-purin-8-yl] methyl] -1-piperidinyl] ethyl] -5H-thiazolo [3, 2-α7-pyrimidin-5-one (Compound 117); 3- (2- (4- [9- (74-fluorophenyl) methyl] -9H-purin-8-yl) -3- (3'-thio) -1-piperidinyl / ethyl) -2-methyl-4H -pyrido [1,2-a] pyrimidin-4-one (Compound 118); 55 * 3 704 3- (2- (4- [9- ([4-fluorophenyl) methyl] -9H-purin-8-yl) sulfonyl] -1-piperidinyl] ethyl] -2-methyl-4H-pyrido [T, 2- α7-pyrimidin-4-one (Compound 119).

Example 33 5 Bromo-1-propylene (1.2 parts), 9-7,4-fluorophenyl) methyl7-N- (4-piperidinyl) -9H-purin-8-amine (3.26 parts), sodium hydrogen carbonate ( 1.5 parts) and ethanol (40 parts) were stirred for 1 hour at reflux temperature. The reaction mixture was filtered hot with diatomaceous earth and the filtrate was evaporated. The residue was dissolved in water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) of acetic acid as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile to give 0.8 parts (22%) of 9- (14-fluorophenyl) methyl-N- [1- (2-propenyl) -4-piperidinyl) -9H-purin-8-amine, m.p. 144.8 ° C (comp. 120).

In a similar manner the following compound was prepared: 4- [9 - [(4-fluorophenyl) methyl] -9H-purin-8-yl] amino] -N- (1-methylethyl) -1-piperidinepropanamide- (E) -2- butene dioate (1: 2) m.p. 202.5 ° C (comp. 121).

Example 34 N- (dihydro-3,3-diphenyl-2 (3H) -furanylidene) -N-methylmethanaminium bromide (3.46 parts), N- (4-piperidinyl) -9- (2-pyridinylmethyl) - A mixture of 9H-purin-8-amine (3.1 parts), sodium carbonate (1.5 parts) and N, N-dimethylacetamide (45 parts) was stirred overnight at 80 ° C. The cooled reaction mixture was poured into water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol saturated with ammonia (95: 5, v / v) as eluent. The pure fractions were collected and ε 5,704,564- [9- (2-furanylmethyl) -9H-purin-8-yl] amino] -Nt-methyl-λ, A-diphenyl-1-piperidinebutanamide (Compound 134): and N , N-Trimethyl-4- (79- [75-methyl-2-furanyl) methyl] -5,9H-purin-8-yl] amino-7 - [(N, N-diphenyl-1-piperidinebutanamide) (Compound 135).

In a similar manner the following compounds were also prepared: N, N, N-trimethyl-4- [9- (2-pyridinylmethyl) -9H-purin-8-10-yl] amino] -N-diphenyl-1-piperidinebutanamide (Compound 136); and 4- (Z- (7β-fluorophenyl) methyl] -N- (N-dimethyl-η 5, Λ-diphenyl-9H-purin-8-yl) oxy] -1-piperidinebutanamide (Compound 137).

Example 35 9- (74-fluorophenyl) methyl-N- (4-piperidinyl) -9H-purin-8-amine (4.9 parts), 4% methanol solution of thiophene (1 part), methanol ( 120 parts), a mixture of 2-propanone (8 parts) and 10% Pd / C catalyst (2 parts) was hydrogenated under normal pressure at room temperature.

After the calculated amount of hydrogen was bound, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile to give 1.5 parts (27.2%) of 9- (74-fluorophenyl) methyl-N- [7- (1-methylethyl) -4-piperidinyl] -9H-purin-8-amine, m.p. 185.6 ° C (comp. 138).

; 30 Example 36

Poly (oxymethylene) (3 parts), (4-fluorophenyl) methyl] -8- (4-piperidinylamino) -7H-purin-6-ol hydrobromide (5 parts), 4% methanol solution of thiophene (1 part) , a mixture of potassium acetate (5 parts), methanol (120 parts) and * 35 10% Pd / C catalyst (2 parts) was hydrogenated! at normal pressure at room temperature. After the calculated amount of 57 Π: 04 hydrogen was bound, the catalyst was filtered off and the filtrate was evaporated. The residue was dissolved in water and the solution was treated with sodium carbonate. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel, eluting with a mixture of trichloromethane and methanol saturated with ammonia (95: 5 by volume). The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 2 parts (56%) of 7- (4-fluorophenyl) methyl] -8 - [(1-methyl-4-piperidinyl) amino] -7H-purin-6-ol, m.p. 255.6 ° C (comp. 139).

In a similar manner the following compound was prepared: 9- (7β-fluorophenyl) methyl-7- [1- (methyl-4-piperidin-15-yl) methyl] -9H-purin-6-ol, m.p. 219.0 ° C (comp. 140). Example 37 2-Ethenylpyridine (1.93 parts), 9- [74-fluorophenyl) methyl] -N- (4-piperidinyl) -9H-purin-8-amine (5 parts) and 1-butanol (80 parts) the mixture was stirred for 20 hours and refluxed overnight. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using trichloromethane and a mixture of ammonia-saturated methanol (95: 5, v / v) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile to give 1 part (15%) of 9- (74-fluorophenyl) methyl] -N- [7- [2- (2-pyridinyl) ethyl] -4-piperidinyl] -9H-purin-8-amine, m.p. 172.3 ° C (comp. 141).

In a similar manner the following compounds were prepared: 9- (2-furanylmethyl) -N- [N- [2- (2-pyridinyl) ethyl] -4-piperidinyl] -9H-purin-8-amine, m.p. 144.5 ° C (comp. 142);

N- [N- [2- (2-pyridinyl) ethyl] -4-piperidinyl] -9- (2-diphenylmethyl) -9H-purin-8-amine, m.p. 152.7 ° C

(compound 143); 58 b;: / 04 Ν- Ϊ- (2- (2-pyridinyl) ethyl] -4-piperidinyl] -9- (2-pyridinylmethyl) -9H-purin-8-amine, mp 163.8 ° C (Compound 144), and 9 - ((75-methyl-2-furanyl) methyl) methyl] -N- [2- (2-pyridin-5-dinyl) ethyl] -4-piperidinyl] -9H-purin-8-amine, m.p. 163.2 ° C (comp. 145).

Example 38 A mixture of 9 - [(4-fluorophenyl) methyl] -N- (4-piperidinyl) -9H-purin-8-amine (5 parts) and methanol (80 parts) was introduced at room temperature with stirring for 30 minutes into oxirane gas. The mixture was stirred for 3 hours at room temperature, then the reaction mixture was evaporated and the residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol saturated with ammonia (95: 5, v / v) as eluent.

The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile to give 2.2 parts (40%) of 4- (9- [7-fluorophenyl) methyl] -9H-purin-8-yl] -amino] -1-piperidineethanol, m.p. 158.7 ° C (comp. 146).

Example 39 2-Chloroacetonitrile (3.22 parts) -9- (4-fluorophenyl) methyl-N- (4-piperidinyl) -9H-purin-8-amine (16 parts), sodium carbonate (12.7 parts) ) and N, N-dimethylformoformate (225 parts) were stirred at room temperature for 6 hours. The reaction mixture was poured into water. The product was extracted twice with trichloromethane. The combined extracts were dried, filtered and evaporated. The residue was crystallized from acetonitrile. The precipitate was filtered off and the filtrate was evaporated, yielding 16 parts of 4- (29- (7β-fluoro-30-phenyl) methyl] -9H-purin-8-yl-7-amino-1-piperidine-acetohitrile (Compound 147).

The following compounds were prepared in a similar manner: 59 85704 5 I ϊ Ϊ 2 3 4

No. L R B -A = A -A = A - m.p.

° C

148 NC-CH2-2-furan ^ -CH2 ~ NH -N = C ~ N = C- 1Q 149 NC- (CH2) 4- 2-uranium-cH ^ · NH -N = CN = C- 150 nc-ch - 2-pyridyl-cH - nh -n = cn = c- • ^ 151 NC-CH2-5'CH3-2-uraniumKnCH2-NH -N = C ~ N = C- 152 NC-CH - 4-FC H ~ CH - 11 CH „-N = CN = C (OCH_) ~ 2 6 4 2 2 3 153 NC-CH - 4-FC, H -CH - Ol -N = CN = C (OH) - 2 6 4 2 2 1C 154 NC-CH - 4-FC, H -CH - CH "-N = CN = C- 15 2 642 2

Example 40 4- (ZT 4 -Fluorophenyl) methyl79H-purin-8-yl-7-20-cunino-7-piperidineacetonitrile (18.2 parts), ammonia-saturated methanol (240 parts) and Raney nickel catalyst (3 parts) ) the mixture was hydrogenated at normal pressure below 20 ° C. After the calculated amount of hydrogen was bound, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from acetonitrile. The product * was filtered off and dried, yielding 16 parts (87.5%) of β- (Ϊ- (2-aminoethyl) -4-piperidinyl-7- [7-fluorophenyl) methyl] -9H-purin-8-amine, m.p. 146.1 ° C (comp. 155).

30 The following compounds were prepared in a similar manner: m 1.5704

r-λ ΐ1 V

'• -'Γα'ΥΙ Ν-' Ν-1 ^ α4 / base 5 I .... - - - - ......— 3 "4 ~ ~ 1

No. L R1 Β -A = Α -A = Α - sp.

L_! F_ 156 Νη2 "(ch2 ^ 2_ 2ίυΓ3η ^ κ'εΗ2_ ΝΗ" N = C_N = C_ - j 157 ΝΗ - (CH) - 2 ^ Γ3ην ^ ί 0Η - ΝΗ -N = CN = C ~ -; 10 I 225 2,158 ΝΗ - (CH 2) -2-pyrrolidinyl - CH_- ΝΗ -N = C ~ N = C- I 222 li 2 1159 NH 2 ~ (CH 2) 2 - 5 "CH 3 '2' * CH 2 ~ ****; 160 NH ~ (CH.) - 4-FC H -CH- CH, -N = CN = C (OCH,) ~ -

I 222 6 4 2 2 S

, 161 NH, - (CH) - 4-FC.H -CH, -CH, -N = CN = C (OH) - 2 2 2 6 4 2 2 162 NH - (CH,) - 4-FC H. -CH, --CH, -N = C ~ N = C- 225 222 642 2

Example 41

A mixture of ethyl 2- [4- [9- (2-thienylmethyl) -9H-purin-8-20-yl] amino] -1-piperidinyl] ethyl] carbamate (10 parts), potassium hydroxide (10 parts) and 2-propanol (240 parts) was stirred at reflux temperature. overnight. The reaction mixture was evaporated. Water was added to the mixture and the mixture was stirred, the product was filtered off and dried, yielding 3.6 parts (56%) of Ν- [ΐ- (2-aminoethyl) -4-piperidinyl] -9- (2-thienylmethyl) -9H-purine. -8-amine (Compound 163).

Example 42 2-Chloropyrimidine (1.7 parts), β- (β- (3β-aminoethyl-3'-yl) -4-piperidinyl) -7- [7-fluorophenyl) methyl] -9H-purin-8-amine ( 5.5 parts), a mixture of sodium hydrogen carbonate (1.5 parts) and ethanol (160 parts) was stirred and refluxed under cooling for 20 hours. The reaction mixture was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. The pure fractions were collected at 61 ° C and the eluent was evaporated. The residue was crystallized from acetonitrile to give 4.5 parts (67%) of 9 - [(4-fluorophenyl) methyl] -N- [N- [2- (2-pyrimidinylamino) ethyl] -4-piperidinyl] -9H. -purine-8-amine, mp 164.1 ° C (comp. 164).

R1 1 10

No. Rl B -Al = A2-A3 = A4- Base or m.p.

salt form 165 2-furanyl-CH - NH - C = N = C- base 135.5 l 2 - 15 166 2pyridinyl- ~ CH2- NH —N = C_N = C— base 140.1 167 2-thienyl.1 CH2- NH -N = C ~ N = C ~ Gm 157.2 168 5 ~ CH-2-uranyl-CH - NH -N = CN = C- erase 174.1 3 11 2 169 4-FC H - CH - CH2 -N = CN = C (OCH3) - base 138.1 170 4-FC H -CH- CH „-N = CN = C (OH)“ base 212.9 6 4 2 2 20 171 4 ~ F “CH -CH - CH_ -N = CN = C- ethanedioate 102.1 6 4 2 2 (1: 3)

Example 43 2-Bromothiazole (3.3 parts), N- [T- (2-aminoethyl) -4-25 piperidinyl] 7-9- [7-fluorophenyl) methyl] -9H-purin-8-amine (5.55 parts) , sodium carbonate (2.12 parts) and a mixture of N, N-dimethylacetamide (18 parts) were stirred and heated at 130 ° C for 20 hours. The cooled mixture was poured into water and the product was extracted with 4-methyl-2-pentanone.

The extract was dried, filtered and evaporated. The residue was purified by chromatography on a silica gel column using a mixture of trichloromethane, methanol and methanol saturated with ammonia (90: 5: 5, v / v) as eluent. The pure fractions were collected and the eluent was evaporated.

The residue was crystallized from acetopitrile. The product was filtered and dried under high vacuum at 100 ° C to give> -704 62 1.8 parts (26.5%) of 9- [7-fluorophenyl) methyl] -N- [7- [2- (2-thiazolylamino) ethyl] “4-Piperidinyl] -9H-purin-8-amine, m.p. 165.4 ° C (comp. 172).

In a similar manner there was also prepared the following compound: 59- (2-furanylmethyl) -N- [N- (5- [2-thiazolyl) amino] pentyl] -4-piperidinyl] -9H-purin-8-amine, m.p. 167.4 ° C (comp. 173)

In a similar manner the following compound was prepared: N2- [2- [4- [9- (2-pyridinylmethyl) -9H-purin-8-yl] -10-amino] -1-piperidinyl] ethyl] -1,3,4-thiadiazole-2; 5-diamine (Compound 174).

Example 44 A mixture of 3-furancarboxylic acid (1.1 parts), 2-chloro-1-methylpyridinium iodide (2.55 parts), N, N-diethylethanamine (2 parts) and dichloromethane (360 parts) was stirred at room temperature for 2 hours. . 3.7 parts of N- [T- (2-aminoethyl) -4-piperidinyl] -9- (T4-fluorophenyl) methyl] -9H-purin-8-amine in dichloromethane were added to the mixture and stirring was continued at room temperature overnight. . The reaction mixture was washed with water. The separated organic layer was dried, filtered and evaporated.

The residue was purified by chromatography on a column of silica gel using a mixture of trichloromethane and methanol saturated with ammonia (95: 5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the salt of (E) -2-butenedioic acid in a mixture of ethanol, 2-propanol and acetonitrile. The salt was filtered off and dried, yielding 2 parts (29%) of N- (2- (4- [9- (4-fluorophenyl) methyl] -9H-purin-8-yl) amino] -1-piperidinyl] -3-ethyl7-3 -furancarboxamide (E) -2-butenedioate (1: 2), m.p. 132.2 ° C (comp. 175).

In a similar manner the following compounds were also prepared: N- (2- (4- (79- (74-fluorophenyl) methyl) -9H-purin-8-yl-3-amino-1-piperidinyl] ethyl] -2-thiophenecarboxamide (E) -2-butenedioate (1: 2) monohydrate, m.p. 135.7 ° C (comp. 176); and 63 1 3 704 N- [2- (4- [9- [7-fluorophenyl) methyl] -9H-purin-8-yl] -amino] -1-piperidinyl] ethyl] -2-thiazolecarboxamide (E) -2-butenedioate ( 1: 2), m.p. 184.0 ° C (comp. 177).

Example 45 2H-3,1-Benzoxazine-2,4- (1H) -dione (1.4 parts), N- [T- (2-aminoethyl) -4-piperidinyl] -9- [74-fluorophenyl] ) A mixture of methyl 7-9H-purin-8-amine (3.7 parts) and N, N-dimethylformamide (45 parts) was stirred at 70 ° C for 4 hours. The cooled mixture was poured into water and the product was extracted with 4-methyl-2-pentanone. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol saturated with ammonia (95: 5, v / v) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the salt of (E) -2-butenedioic acid in ethanol. The salt was filtered off and dried, yielding 4.3 parts (50%) of 2-amino-N- [2- (4- [9- (14-fluorophenyl) methyl] -9H-purin-8-yl] -an27- piperidinyl7-ethyl-7-benzamide (E) -2-bu-20-dione dioate (2: 5), m.p. 164 ° C (comp. 178).

Example 46

Isothiocyanatoethane (0.7 parts), N- [1- (2-aminoethyl) -4-piperidinyl] -9- [4-fluorophenyl) methyl] -9H-purin-8-amine (3.7 parts) and tetrahydrofuran (90 parts). part) the mixture was stirred at room temperature for 4 hours. The mixture was evaporated and the residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol saturated with ammonia (95: 5, v / v) as eluent. The first fraction was collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.3 parts (29%) of N- (2- [4- (4- [7-fluorophenyl) methyl] -9H-purin-8-yl] amino] -1-piperidinyl] ethyl] N-methyl. -: thiourea, m.p. 205.5 ° C (comp. 179).

In a similar manner, the following compound was prepared: 64 L., 704 N- (2- (4- [9- (74-fluorophenyl) methyl] -9H-puria-8-yl] methyl] -N'-Piperidinyl-ethyl-7-N '- ethyl urea (compound 180). Example 47 To a stirred and cooled (-10 ° C) mixture of N, N'-methanetrayraybis / cyclohexanamine7 (5.6 parts), carbon disulfide (13.9 parts) and tetrahydrofuran (90 parts) was added portionwise 10 parts of N- / T- (2-aminoethyl) -4-pi ~ peridinyyli7 9- / 4-fluorophenyl) metyyli7-9H-purin-8-amine. After the addition was complete, the temperature was allowed to rise to room temperature and the reaction mixture was evaporated to give 16 parts of 9 - [(4-fluorophenyl) methyl] -N- [7- (2-isothiocyanatoethyl) -4-piperidinyl] -9H-purine-8 -amine (compound · · 1 81).

3,4-pyridinediamine (2.95 parts), 9- [7,4-fluoro-16-phenyl) methyl] -N- [1- (2-isothiocyanatoethyl) -4-piperidinyl] -9H-purin-8-amine (16 parts) and tetrahydrofuran (90 parts) were stirred and refluxed overnight. The reaction mixture was evaporated. The residue was purified by chromatography on a column of silica gel using a mixture of trichloromethane and methanol saturated with ammonia (95: 5, v / v) as eluent.

The pure fractions were collected and the eluent was evaporated, yielding 10.5 parts of N- (4-amino-3-pyridinyl) -N '- [2 - phenyl (4-fluorophenyl) methyl] -9H-purin-8-yl] amino. -piperidinyl7ethyl7thiourea (Compound 182).

N- (4-amino-3-pyridinyl) -N1- [2- [4- [9- [74-fluorophenyl) methyl] -9H-purin-8-yl] amino] -1-piperidinyl] ethyl] fluorourea (10, A mixture of 5 parts), excipient oxide (6 parts), sulfur (1 part) and ethanol (120 parts) was stirred and refluxed overnight. Reaction-

(A

the mixture was filtered by Hyfloller hot. The filtrate was evaporated. The residue was purified by chromatography on a column of silica gel using a mixture of trichloromethane and methanol saturated with ammonia (90:10) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the salt of 65.5 g of (E) -2-butenedioic acid in ethanol. The salt was filtered off and dried, yielding 4 parts (17%) of 9 - ((4-fluorophenyl) methyl] -N - [(N- [2- (1H-imidazo [4,5-c] pyridin-2-yl) amino] ethyl] -4 -piperidinyl 7-9H-purine-5-n-8-amine- (E) -2-butenedioate (1: 3) monohydrate, m.p. 191.0 ° C (comp. 183).

Example 48

To a sodium methoxide solution prepared in advance from 25 parts of sodium and 400 parts of methanol was added 49.4 parts of 6-chloro-9- [4-fluorophenyl) methyl] -8- [N- (phenylmethyl) -4-piperidinyl] methyl] -9H-purine. . After stirring for 8 hours at reflux temperature, the reaction mixture was cooled and 1000 parts of water were added thereto. The precipitated product was filtered off and dried, yielding 34.5 parts (70.4%) of 9-Z14-fluorophenyl) methyl-6-6-methoxy-8- [2- (phenoxymethyl) -4-piperidinyl] methyl] -9H-purine (compound 184).

Example 49 A mixture of 6-chloro-9- (4-fluorophenyl) methyl] -8- [N- (phenyl-20-methyl) -4-piperidinyl] methyl] -9H-purine (3 parts) and a 1-m hydrochloric acid solution (50 parts) was refluxed. 1.5 hours. The cooled mixture was made alkaline with ammonium hydroxide. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was crystallized from a mixture of acetonitrile and ethanol. The product was filtered off and dried, yielding 1.5 parts (52%) of 9 - [(4-fluorophenyl) methyl] -1,9-dihydro-8H- [N- (phenylmethyl) -4-piperidinyl] methyl] -6H-purine. -6-one, m.p. 197.0 ° C (comp. 185). Example 50 9- (N- (4-fluorophenyl) methyl] -8- [N- [2- (4-methoxy-phenyl) ethyl] -4-piperidinyl] ethyl] -9H-purin-6-ol (2.7 parts) and a mixture of 48% aqueous HBr (75 parts) was stirred at 80 ° C for 4 hours. The mixture was evaporated, the residue was dissolved in water and the solution was treated with sodium carbonate. The product was extracted with trichloromethane. The extract was 66%, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol saturated with ammonia (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from ethanol and acetonitrile. The product was filtered off and dried, yielding 1 part (738.6%) of 9- (74-fluorophenyl) methyl-7- [N- (2- (4-hydroxyphenyl) ethyl] -4-piperidinyl] ethyl] -7H-purin-6 -olia, sp. 215.7 ° C 10 (compound 186).

In a similar manner there was also prepared the following compound: 4- (4 - [([4- [7-fluorophenyl] methyl] -7H-purin-8-yl) -amino] -1-piperidinyl] methyl] phenol, m.p. 228.1 ° C (comp. 187).

In a similar manner there was also prepared the following compound: 2- (2- [4- (9- [7-fluorophenyl) methyl] -9H-purin-8-yl] methyl] -1-piperidinyl] ethyl] phenol (Compound 188).

Example 51 To a solution of 4- (7 - ([(4-fluorophenyl) methyl] -9H-purin-8-yl) -20-thio [1- (7,4-methylphenyl) sulfonyl] piperidine (7.2 parts) and dichloromethane (195 parts) was added with stirring. dropwise a solution of 3-chlorobenzeneperic acid (7 parts) in 65 parts of dichloromethane. After the addition was complete, stirring was continued at room temperature for 2 hours.

The mixture was washed with sodium carbonate solution and twice with water, dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 3 parts (40%) of 4- (79- (74-fluorophenyl) methyl] -9H-purin-8-yl] sulfonyl-1- (74-methyl-phenyl) sulfonyl] piperidine (Compound 189).

Claims (11)

67 I 2 7 O 4 Claims Analogous process for the preparation of therapeutically useful (4-piperidinylmethyl and hetero) purines of the formula I f R1 Γ'Λ h LN) —B— (f \ —- A1 10 w » A 1, A 4 = A 3 where -A 1 = A 2 -A 3 = A 4 - is a divalent group of formula 15 a-1 or a-2 -N = CH-N = CH- (a-1) -CH = N-CH = N- (a-2) wherein one of the hydrogen atoms in the group of formula a-1 or a-2 may be replaced by C 1-4 alkyl, C 1-4 alkyloxy or hydroxy, R 1 is C 1-4 alkyl, C 3-6 cycloalkyl or Ar 1 -C 1-4 alkyl, wherein Ar 1 is thienyl, pyridinyl, pyrazinyl, thiazolyl, furanyl, C 1-4 alkyl substituted furanyl, phenyl or phenyl substituted by halogen, C 1-4 alkyl or C 1-4 alkyloxy; R 2 is hydrogen or C 1-6 alkyl; B is -CH 2 -, -s-, -O- or -NH-; 30. is a group of formula b-11L-TC.Ha. - (b-1) wherein s is an integer from 1 to 6, 35. is -Y- or -ZC (= X) -Y-, wherein ·· Y is a direct bond or NR3, £ 5,704 68 Z is a direct bond or NR 3 and X is O or S, wherein R 3 is hydrogen or C 1-6 alkyl; and L1 is hydrogen; hydroxy; C ^ alkyloxy; C2-5 alkenyl; phenyl-5; phenyl substituted by hydroxy, amino, C 1-6 alkyl or C 1-4 alkyloxy; furanyl; thienyl; pyridinyl optionally substituted with amino; pyrimidine-pyridinyl; morpholinyl; 2,3-dihydro-l, 4-benzodioxinyl; 2-oxo-2H-l-benzopyranyl; thiazolyl; 4,5-dihydro-5-oxo-1H-tetrazolyl substituted with C 1-4 alkyl; or a group of formula e-1, e-4, e-7 or e-8 / vV Y-VN ^ CH) υγ- ογ <'«0 oa HH" -7> OrV ° ^ N wherein G2 is - CH = CH-CH-CH-, - (CH2) 4- or -S-CH = CH-, and their pharmaceutically acceptable acid addition salts and possible stereochemically isomeric forms, characterized in that a) N-alkylating piperidine of formula 1-cl HD (Ic-1): Y: 30 wherein D is a group of formula R2 R1 '· r \ A i • 35 N \ / b ~ ^ - N— \ I A4 = A3 69 15/04 wherein -A1-A2-A3-A4-, R1, R2 and B have the same meaning as in formula I, in an inert organic solvent with a reagent of formula VII-a 5 L1-T-CeH2e-W (VII-a) wherein L1, T and s are as defined in formula I and W is a reactive leaving group; b) alkylating piperidine of formula Ic-2 H-T2-C.H2, -D (Ic-2) wherein T2 is -NR3- or -NR3-C (= X) -Y- and s, R3, X and Y are as defined in formula I, in an inert organic solvent with a reagent of formula VII-b L1 '* - »» (VII-b) wherein L1-a is pyrimidinyl or thiazolyl and W is a reactive leaving group, to give a compound of formula Ibla L1 - ^ - C.Hj.-D (Ibla); C) Reducing N-alkylating piperidine of formula Ic-1 HD (Ic-1): in a reaction-inert solvent with a carbonyl compound of formula VIII iZ-TC.H 2 -O (VIII) 35 which the compound of formula VIII is a reagent of formula 70 85/04 11 'Τ-ΟβΗ2, * 1, in which L1, T and s have the same meaning as in formula I and in which the group -CH2- is replaced by a carbon-5-yl group; d) reacting an amine of formula XI (XI) 10 in which L1 is as defined in formula I in a reaction-inert solvent with an isocyanate or isothiocyanate of the formula If X = C = NC, H2.-D (If) wherein X and s are as defined in formula I to give a compound of formula Ib-4 L-NH-C (> X) -NH-C, H2.-D (Ib-4); E) reacting an isocyanate or isothiocyanate of formula L1-N = C = X: wherein L · 1 and X are as defined in formula I in a reaction inert solvent with an amine of formula lc-4-30 H2N-C, H2.-D (Ic-4) wherein s is as defined in formula I to give a compound of formula Ib-4; f) reacting a reagent of formula XIII 35 1 / -0 (®X) -OH (XIII) 71 I ', 5 7 O 4 wherein L1 and X are as defined in formula I, in a reaction-inert solvent of formula Ic-4 after conversion of the OH group in a compound of formula XIII to a reactive leaving group, or by reacting a reagent of formula XIII with an amine of formula Ic-4 in the presence of a reagent capable of forming esters or amides to give a compound of Formula Ib-6-a 10 1 -O (= X) -NH-C. H 2b-D (Ib-6-a); g) subjecting my intent to formula XIV L1-T-C2-6-alkenediyl-H (XIV) to react in a reaction-inert solvent with piperidine of formula H-D (I-c-1) to give a compound of formula I-g L1-T-C2-6-alkanediyl-D (I-g); H) reacting a piperidine of formula Ic-1 in a reaction inert solvent with an oxirane of formula XV 30 H 2 C-CH 2 (XV) to give a compound of formula Ih HO-CH 2 -CH 2 -D (Ih); Or i) silylodesulfurizing a thioamide of formula 5 nh 2 (1H s (XXXVn) H 10 in an inert solvent with a suitable alkyl halide, metal oxide or metal salt to give a compound of formula Ii-11 15 H i057_NH "c, Hi 'D <Η'η) · 20 or optionally the compounds of formula I are converted into each other by art-known modification methods, and if desired the compounds of formula I are converted into therapeutically active, non-toxic acid addition salts by treatment with a suitable acid, or the acid addition salt is converted into the free base with an alkali, and / or stereochemically isomeric forms of the compounds of formula I are prepared. KN LN) —B — S \ —A1 10 \ / \\ lf ^ A2 {'I' a4 = a3 color -A1®A2-A3 * A4- is a bivalent group with formula a-1 15 or a-2 -N = CH-N = CH- (a-1) -CH = N-CH = N- (a-2) 20 colors of a hydrogen atom in a group of groups a-1 or a-2 can be substituted with C 1-4 alkyl, C 1-4 alkyloxy or hydroxy; R 1 is C 1-4 alkyl, C 3-6 cycloalkyl or Ar 1 -C 1-4 alkyl, color Ar 1 is thienyl, pyridinyl, pyrazinyl, thiazolyl, furanyl, with C 1-4 alkyl substituted with furanyl, phenyl or phenyl with substituents halogen, C 1-4 alkyl or C 1-4 alkyloxy; R 2 is C 1-6 alkyl; B is -CH 2 -, -S-, -O- or -NH-; 30 A group of compounds of formula b-1 L'-T-C.H, .- (b-1) color is given in pages 1-6, 35 T är -Y- or -ZC (»X) -Y-, color Y är en direct binding or NR3, 74 / ϋ 4 Z Mr en direct binding NR3 and X Mr 0 or S, colors R3 Mr vMte or C alkylene; and L1 Mr vMte; hydroxl; C ^ -alkyloxi; C 2-5 alkenyl; biphenyl; en 5 is hydroxy, amino, C 1-4 alkyl or C 1-4 alkyloxy substituted phenyl; furanyl; tlenyl; and with amino optionally substituted pyridinyl; pyrimidinyl; morpholinyl; 2,3-dihydro-1,4-benzodioxinyl; 2-oxo-2H-l-bensopyranyl; tiazo-lyl; and C 1-6 alkyl substituted with 4,5-dihydro-5-oxo-1H-10 tetrazolyl; or groups of formulas e-1, e-4, e-7 or e-8 I ^ VV lOLL JL (e'4) “S T 00-M rx> »wi 20 colors G2 Mr -CH = CH-CH = CH-, - (CH2)« - or -S-CH = CH-, as well as a pharmaceutically acceptable sugar addition and eventual stereochemical isomer dMrav, kMnnetecknat V 25 dMrav, att a) N-alkyler and piperidine with formula Ic-1 y: HD (Ic-1) 30 color D Mr en group, with formula R2 Ri / -k I ....: V_V \ _f 35 N ~ \! a4 = a3 G 5 704 75 color -A1 = A2-A3 = A4-, R1, R2 and B betecnar sanoma som i for-Meln I, i and inert organic solvents with a reagent of formula VII-a 5 iZ- TC.Hj.-W (VII-a) color L1, T and the same sample as i and W are en reactive groups; b) alkyl and piperidine with the formula Ic-2 10 H-T2-C, H2, -D (Ic-2) color T2 and -NR3- or -NR3-C (= X) -Y- and s, R3, X and Y is the same as in formula I, and inert organic solvents with reagents of formula VII-b ^ '• -W (VII-b) color L1' * with pyrimidinyl or thiazolyl and with reactants 20 group, varvid erhälls en förening med formeln Ibla Li-_T2_CeH2, -D (Ibla); C) N-alkylated reductive and piperidine with formula 1-cl HD (Ic-1) 30. and reaction-free solution with carbonyl salt-Ning with formula VIII L1-TC.H2..J-0 (VIII) 35 Formula VIII is a reagent of Formula 76 and 5 7 O 4 color L1, T and the same mixture as Formula I and a color group -CH2- substituted with a carbonyl group; 5 d) the amine to the amine of formula XI Ι / -ΝΗ2 (XI) vari L1 is selected from the group consisting of i and formula I, i and the reaction-10 inert solution with isocyanate or isothiocyanate with formula If X = C = N-CeH2.-D (If) 15 are X and the same mixture as in Formula I, which is different from the formulation of Formula Ib-4 L-NH-C (* X) -NH-C, H2, -D (Ib-4); 20 e) a mixture of isocyanates or isothiocyanates with the formula L1-N = C = X 25 vari L1 and X in the same manner as in formula I, and in the reaction of the reaction medium with the amine of formula Ic-4 H2N-C.H2.-D ( Ic-4) 30 variants of the same formula as in Formula I, including a mixture of Formula Ib-4; f) omsätter ett reagens med formuleln XIII 35 L1-C (= X) -OH (XIII) £ 3,704 77 color L1 and X in the form of a compound of formula I, a reaction medium with an amine of formula Ic-4, a white space, a sedan and a mixture of formulas XIII närvarande OH-Gruppen överförts account en reactivation av-5 ägsnande grupp, eller genom att omsätta ett reagents with formulas XIII med et Amin med formuleln Ic-4 i närvaro av ett sädant reagents which are used to form a picture of esters or amides, colors are different förening med formeln Ib-6-a 10 L1-C (-X) -NH-C, H2, -D (I-b-6-a); g) a mixture of the alkene with the formula XIV L1-T-C2.6-alkenediyl-H (XIV) 15 and the reaction-inert solution with the piperidine with the formula HD (Ic-1) 20 colors different from the formulation with the formula Ig - I ^ - T-C 1-6 alkanediyl-D (Ig); ... 25 h) addition of piperidine with formula I-c-1 and reaction reaction solution with oxirane with formula XV 30 ^ The H2C-CH2 (XV) colors are different from those of formula I-h. HO-CH2-CH2-D (I-h); 35 or 78 ε 5 7 O 4 i) a cyclodesulfurer with thioamides of formula XXXVII NH2 and 1 S (XXXVn) 5. yK ^ CjHjj-D ^ NH H i and reaction reactions with a further solution of heat-treated alkyl halides, metal oxides or metal salts, varvid 10 erhälls en förening med formuleln Ii-11 H i0 ^ / ~ nh ~ c, h2, "d 15 eller eventuell överför föreningar med formuleln I account varandra medelst inom omrädet kända gruppöverfö-ringfarfaranden, och ifali önskvärt, överför account for therapeutic activity, giftfria syraad-20 ditiossalter genome to be used in the presence of syrup, or in addition to the use of alkali in the form of alkali, and / or stereochemically isomeric isomeric compounds of formula I. • «· • · * Λ 0